The molecular basis of genetic disease Corinne D. Boehm and Haig H. Kazazian Jr Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Current Opinion in Biotechnology 1990, 1:180-187

Introduction The spectrum of genetic disease is broad, extending from traits for which we are at the complete mercy of a change in one gene (single-gene disorders such as Huntington's disease, neurofibromatosis, and Duchenne muscular dystrophy) to those which are affected by the interaction of several genes as well as environmental influences (polygenic or multifactorial traits such as schizophrenia, heart disease, and cancer). Initial efforts to identify genetic defects focused on the single-gene disorders; these are easier to identify because of their near absolute correlation with a certain health state. Genes focused on in the 1980s included those for a- and ]3-globin (defects producing thalassemia), Factors VIII and XI (hemophilia A and B, respectively), phenylalanine hydroxylase (associated with phenylketonuria), dystrophin (Duchenne/Becker muscular dystrophy) and low-density lipoprotein (LDL) receptors (hypercholesterolemia). In Certain instances, the identity of a gene responsible for a given disorder was easy to predict because the affected protein was already known (globin defects, hemophilia A and B, and phenylketonuria): in other cases, the identification of the genetic defect preceded and allowed the identification of the affected protein, a process known as reverse genetics or positional gene cloning. For instance, it was the identification of mutations which produce Duchenne and Becker muscular dystrophy which led to the identification of dystrophin as the affected protein in these diseases. The application of reverse genetics to the discovery of disease-producing genes has relied heavily, although not exclusively, on gene mapping. This is the process of identifying the gross chromosomal location of a disease-producing gene by linkage analysis. Next, tedious examination of the target region is carried out for tell-tale signs of potentially important candidate genes. Sequences which might be considered for very close examination can be identified by a number of different strategies; these include identification of the following: HTF islands (Hpa II tiny fragments) containing many CpG dinucleotides, sequences conserved between species, an RNA transcript or stretches of DNA which give a long open reading frame. Ultimately, the mutations within the gene that causes the disease state need to be discovered.

The characterization of genetic defects is valuable in several respects. Firstly, it allows a better understanding of normal biological processes and identification of those sequences which are important for normal gene function. Secondly, it leads us to a better understanding of particular diseases and enables us to devise more rational treatment for affected individuals. Thirdly, it allows more accurate diagnosis of a genetic disease, not only in affected individuals but also in asymptomatic carriers. Following is a brief summary of the progress that has been made in the molecular analysis of human genetic disease between April 1989 and October 1990. We have not included new alleles found in genes already known to produce disease as this would produce a very long list and is beyond the scope of this review.

Linkage determinations Charcot-Marie-Tooth disease For some time, linkage between a locus for the autosomal dominant hereditary motor and sensory neuropathy Charcot-Marie-Tooth disease (CMT) and the Puffy blood group on chromosome 1 has been known. However, this linkage was not present in a large number of families with CMT disease. This particular puzzle was solved last year by identification of a separate locus for CMT disease to the pericentric region of chromosome 17 [1 ..]. Since that description, linkage of CMT to this latter locus has been described in an additional 15 CMT families [2,3]. CMT disease has now been subdivided clinically into CMTla (chromosome 17 locus) and CMTlb (chromosome 1 locus).

Spinal muscular atrophy The term spinal muscular atrophy encompasses a wide range of clinical disorders invoMng degeneration of anterior horn cells of the spinal coM. Severity of disease ranges from the severe type I (Werdnig-Hoffman) to the milder chronic types II (intermediate Werdnig-Hoffman) and III (Kugelberg-Welander). Recently, two groups [4..,5 "'] have shown strong linkage of the locus responsible for types n and III disease to chromosome 5q (es-

Abbreviations CFTR--cysticfibrosis transmembraneregulator;CMT--Charcot-Marie-Toothdisease;LDL--Iow-density[ipoprotein; NF-l--neurofibromatosis type 1; RFLP--restrictionfragment length polymorphism. 180

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The molecular basis of genetic disease Boehm and Kazazian timated at 5q11-5q13) and one of these groups has also shown linkage of the severe type I to the same region [6"]. In total, 41 families were examined and in only two of these was the linkage between the disease locus and the 5q locus not documented. It is possible that disease was misdiagnosed in these families or perhaps they have a genetically distinct form of the disease.

lies with two or three affected siblings produced a maximal lod score of 7.37 at a theta value of 0.00 with locus D5S72. Several genes with a possible role in this disease (including those for growth factors, growth factor receptors, and hormone receptors) are known to be located within this region. The gene for osteonectin lies more distally on chromosome 5.

Primary osteoarthritis

Hereditary spherocytosis

In one large family, inheritance of the phenotype of primary osteoarthritis was linked to the COL2AI collagen gene on chromosome 12q [7"]. However, the nature of the defect producing this disease was not characterized, nor was it proven that mutation in the COL2M gene was the cause of disease.

This autosomal dominant disease is characterized by erythrocytes with a spherical (rather than biconcave) appearance. Recently, this trait has been linked to the gene for ankyrin (lod score of + 3.63) in one large kindred with the disease [14].

Friedreich's ataxia

Mutations identifying disease genes

The locus responsible for this autosomal recessive disease was described in 1988 as being near the centromeric region of chromosome 9 [8]. However, the question of genetic heterogeneity in this disease arose because of variation in the age of onset and clinical manifestations. Linkage analysis in 80 families from European, FrenchCanadian, Acadian, and Spanish populations with Friedreich's ataxia showed no instances of recombinations with the MCT112 locus on chromosome 9 [9"]. This analysis generated a maximal lod score of 25.09 at a recombination fraction of 0.00. These data strongly suggest that either a single locus is responsible for the disease, or that one locus in predominatly involved. Thus, while this disease is clinically heterogeneous, it is almost always due to a gene or set of genes located near the centromere on chromosome 9.

Complete X-linked congenital stationary night blindness The X-linked form of complete stationary night blindness is associated with myopia; an autosomal dominant form of the disease is not. Tight linkage of this disease genotype with a DNA marker at Xp11.3 was found in seven multigenerational families [ 10].

Cystic fibrosis The gene for cystic fibrosis was cloned in mid-1989 by groups at the University of Michigan and The Hospital for Sick Children, Toronto [15"',16"',17"']. The gene spans 250 kilobases and contains 27 exons. It encodes a m e m b e r of the P-glycoprotein or ATP-binding transport super-family which is thought to be involved in chloride transport in epithelial cells and is referred to as the CFTR (cystic fibrosis transmembrane regulator) gene. A major mutation, deletion of three nucleotides eliminating phenylalanine at residue 508 in the first nucleotide-binding fold of the protein, accounts for roughly 70% of cases of cystic fibrosis worldwide. By September 1990s the cystic fibrosis genetics consortium had found about 60 other mutant alleles in various ethnic groups, no one of which accounts for more than 2% of cystic fibrosis genes. A mutation hot-spot has been found in the first of two nucleotide-binding folds in the CFTR protein [18]. Recendy, the gene has been transfected into epithelial cells from cystic fibrosis patients using viral vectors and this resulted in correction of the chloride transport defect in vitro [ 19 ",20 "'].

Alport syndrome Malignant hyperthermia

Diastrophic dysplasia

Three different alterations in the newly discovered Xlinked COL4A5 gene have been identified in each of three families with X-linked Alport syndrome [21 ..,22 "-24"]. This collagen gene is a component of a basement membrane protein which had previously been implicated in Alport syndrome. The three alterations include an intragenic deletion, a single amino acid substitution (cysteine to serine) in a highly conserved non-collagenous domain of the protein, and an as yet uncharacterized mutation which manifests as an absence of a lightly hybridizing Taq I fragment on Southern blot analysis.

The locus for this relatively rare autosomal recessive form of osteochondrodysplasia has been localized to chromosome 5 using close linkage to three chromosome 5 restriction fragment length polymorphisms (RFLPs) [13 "']. Linkage analysis including 84 individuals from 13 fami-

Two groups have isolated the same candidate gene for Wilms' tumor at chromosome 11p13 [ 2 5 " , 2 6 " ] . This

In three large Irish families with malignant hyperthermia as an autosomal dominant trait, linkage analysis localized the gene responsible to chromosome 19q12-13.2 [11 "]. A candidate gene for this disorder, the skeletal muscle ryanodine receptor, has recently been localized to chrom o s o m e 19cen-q13.2 and thus may have a role in this disorder [12].

Wilms' tumor



Mammalian gene studies gene encodes a zinc-finger protein which is likely to be a transcription factor. The idea that this gene is important in the formation of Wilms' tumors is supported by several observations. Firstly, the gene is transcribed in a specific pattern in each of the developing kidneys, the organ in which the tumor arises, and genitalia, as well as in the tumor itself [27"]. Secondly, loss of the candidate gene or a part of it (25 base-pairs) has been associated with Wilms' tumors [28 °]. Interestingly, the deletion was not present in the germ line of the patient with the 25 bp intragenic deletion.

Neurofibromatosis type 1 Two groups have isolated and are characterizing the gene responsible for neurofibromatosis type 1 (NF-1) [ 2 9 " - 3 2 " ] . One group has named this gene NFILT and the other TBS (translocation break-point region). Several different mutations have been shown in the gene isolated by these groups, including: 17q translocation breakpoints within the gene; insertion of a 500 base Alu element within the gene that is associated with a spontaneous case of NF-1; partial gene deletion; and nucleotide alterations within the gene (including one stop mutation). The gene has been shown to be active in many tissues including peripheral nerves, lymphoblasts, brain, spleen, and lung. Three other transcribed genes (one of which was originally a NF-1 candidate gene) lie within an intron of the NF-1 gene. All three are transcribed in the opposite orientation to the NF-1 gene. The encoded protein has significant homology with mammalian cytoplasmic GAP proteins which are involved in cell growth through interacting with proteins such as the ras gene product.

disease further implicates the COL2A1 gene as the locus responsible [38].

Xeroderma pigmentosum-Band Cockayne's syndrome Microinjection of mRNA from a functional DNA helicase gene (the recently cloned ERCC-3 gene) corrected the DNA repair defect in cells from an individual with B complementation xeroderma pigmentosum who also has Cockayne's syndrome [39"]. However, this mRNA did not correct the defect in cells from the other seven complementation groups (A, C, D, E, F, G and H). The correction was accomplished following microinjection of ERCC-3 mRNA into homopolykaryons of cells from a patient with xeroderma pigmentosum-B. The ERCC3 mRNA restored the ability of the cell to perform ultraviolet-induced unscheduled DNA synthesis i n vitro. The mutation responsible for the corrected defect was an RNA-splicing defect in a consensus acceptor splice site which produced an mRNA with a four-base-pair insertion. This insertion destroys the open reading frame.

Marfan's syndrome Linkage of the Marfan's syndrome locus to chromosome 15q has been demonstrated in all of five informative Marfan's syndrome pedigrees which were examined [40-]. The maximal lod score was theta value 0.0 ( + / - 0 . 1 1 ) with the three chromosome 15 markers, D15S45, D15S29, and D15S25. The question of genetic heterogeneity in this disease remains to be explored. Recent functional studies have implicated the fibrillin gene as deficient in individuals with this disease [41 "] but the chromosomal location of this gene is not yet known.

Familial hypertrophic cardiomyopathy This condition seems to result from a variety of molecular defects. One large kindred with hypertrophic cardiomyopathy as an autosomal dominant trait showed very tight linkage of the responsible gene (lod score of + 9.37 at a theta value of 0) to chromosome 14ql [33 "]. The gene encoding the [3 cardiac myosin heavy chain is a candidate because it is located on chromosome 14q. In another family with the disease a hybrid gene of the a/[3 cardiac myosin heavy chain was the molecular cause of the cardiomyopathy [34"]. Several sporadic cases were found to be the result of deletions within mitochondrial DNA [35].

Spondyloepiphyseal dysplasia Mutations within the COL2A1 collagen gene have been shown to be the cause of spondyloepiphyseal dysplasia in several instances. These include a 390 bp deletion of exon 48 (36 amino acids) which leaves the reading frame of the mRNA intact [36"]. In another case, a tandem duplication of 45 base pairs, also within exon 48, results in the addition of 15 amino acids [37]. Furthermore, altered electrophoretic mobility of the type II collagen of costal cartilage from 12 individuals with various forms of the

Mechanisms producing genetic disease Imprinting Prader-Willi and Angelman syndromes are clinically different diseases which result from deletions that are similar in location (chromosome 15) and extent. However, Prader-Willi syndrome results from inheritance of only maternal chromosome 15 sequences, whereas Angelman syndrome follows inheritance of only paternal chromosome 15 sequences. This suggests that the remaining (non-deleted) gene in an individual with Prader-Willi or Angelman syndrome has different functions depending on the parent from which it was inherited. This hypothesis has been further supported by the discovery of two cases of non-deletion Prader-Willi syndrome which were associated with maternal heterodisomy for the critical region of chromosome 15 (the inheritance by the affected individuals of both copies of the maternal chromosomes 15 and no copies of a paternal chromosome 15) [42.]. Both non-deletion and deletion cases of Prader-Willi syndrome seem to occur as a result of not inheriting paternal sequences from the critical region of chromosome 15. In contrast non-deletion Angelman syndrome has been seen following inheritance of critical regions from both

The molecular basis of genetic disease Boehm and Kazazian 183 the mother and the father (Knoll et aL, A m J H u m Genet 1990, 47: Abs 883).

Somatic mosaicism Somatic mosaicism was recently documented in a man with mild osteogenesis imperfecta who had a son with a perinatal lethal form of the disease [43 "]. DNA from both individuals contained the same lethal single nucleotide change producing an amino acid substitution. However, polymerase chain reaction analysis showed varying prevalence of this mutation in different cell types from the father (50% in fibroblasts, 27% in blood, and 37% in sperm) explaining his survival.

Mutations in nuclear DNA affecting mutations in mitochondrial DNA Several different mitochondrial myopathies (including Leder's hereditary optic neuropathy, infantile bilateral striatal necrosis, myoclonic epilepsy and ragged red musd e disease) result from mutations within mitochondrial DNA. These diseases are only inherited through the maternal lineage as mitochondria are only inherited from the mother. Deletions within mitochondrial DNA have also been found in individuals with mitochondrial myopathies who have a spectrum of neuromuscular symptoms. Recently a family with an autosomal dominant form of inherited mitochondrial myopathy was evaluated [44.]. Affected individuals in the family were found to have multiple, different mitochondrial DNA deletions, all of which affected the same region. A common 3' end of the break-point was identified within a 12 nucleotide cluster in all 19 deletions from mitochondrial DNA examined; these were from four affected family members. The break was in the D-loop region of mitochondrial DNA where protein-DNA interactions that affect mitochondrial DNA replication and transcription are thought to occur. Presumably, a mutation within the nuclear DNA, which is inherited in this family as an autosomal dominant trait, has its pathological effect by promoting de novo deletions within mitochondrial DNA.

More than one phenotype caused by mutation at a single gene Many examples exist of both genetic 'homogeneity' and genetic 'heterogeneity' within disease groups. The former are situations in which a single locus is apparently responsible for an inherited disease in all cases despite variation in clinical severity among them. In the latter, different loci are responsible for a seemingly identical clinical state in different individuals (these have also been called genocopies). Recently two examples of different diseases being caused by different mutations within the same gene, have been described. In one family, a single nucleotide substitution at position 382 of the cz-subunit of the insulin receptor gene resulted

in insulin-resistant diabetes mellitus [45"]. Presumably post-translational modification was impaired resulting in fewer receptors on the cell surface. In another family, a single nucleotide substitution at position 233 in the czsubunit resulted in leprechaunism [46.]. This mutation apparently lies within a region of the gene coding for a protein involved in transmitting the insulin-binding signal to the tyrosine kinase domain. In both of these cases, imprinting could not explain the different phenotypes because the situations involve a consanguineous mating in which the parents were both shown to be autosomal recessive carriers of the defect. Mutations in the COL2A1 collagen gene which have previously been shown to be responsible for the Stickler syndrome [47] provide another example of this phenomenon. During the past year several instances of a mutation in this gene were also found to result in spondyloepiphyseal dysplasia [36",37]. Linkage studies suggest this gene is also affected in one family with osteoarthritis [7"].

Unequal sister chromatid exchange Three instances have been described in which a dystrophin gene duplication was seen in a woman on a chromosome she had inherited from her father (as demonstrated by RFLP haplotype analysis) [48] which did not contain the duplication in the father's DNA. It is most likely that these duplications originated in the fathers of these women, by the mechanism of unequal sister chromatid exchange. Homologous chromosome recombination would not be an explanation because males have only one X chromosome.

Susceptibility genes in multifactorial diseases Multiple sclerosis A recent study analyzed the inheritance pattern of RFLP haplotypes of the T-cell receptor 13chain gene in 40 families in which two or more siblings were affected with multiple sclerosis [49]. Within families, the affected sibling pairs showed a higher-than-expected rate of inheritance of identical haplotypes from their parents. This phenomenon was not seen in their unaffected siblings. In addition, particular specific T-cell receptor [3 chain haplotypes were over-represented among haplotypes being inherited by multiple sclerosis sibling pairs as compared with those parental haplotypes which were not inherited by the multiple sclerosis pairs. The data point to a locus (either the T-cell receptor [3 chain gene or a closely linked gene) which plays a role in an individual's susceptibility to multiple sclerosis. The authors calculated that this locus accounts for one sixth of the increased risk that siblings of individuals with multiple sclerosis have for developing the disease.


Mammalian gene studies Non-syndromic cleft lip (with or without cleft palate) In one recent study [50] the authors examined 12 RFLPs at five loci which are involved in palatogenesis in rodents. They compared the frequencies of allele types at these RFLPs in 80 individuals with non-syndromic cleft lip (with or without cleft palate) and in 102 controls. A significant difference in frequencies was observed for two RFLPs at the transforming growth factor-0t locus. This association implicates this gene, or a closely linked gene, in normal lip and palate development; it also suggests that there may be one allele type in the general population that produces a susceptibility to clefting and this allele is 'hitchhiking' with a particular RFLP haplotype.

Heart disease It has been shown previously that increased levels of circulating LDL are a risk factor for coronary heart disease [51]. Mutations in the LDL receptor gene have been shown to account for the autosomal dominant form of hypercholesterolemia [52], a single gene disease which produces coronary artery disease. More recently [53], investigators used an antibody to apolipoprotein B to measure the relative amounts of LDL which were translated from maternally versus paternally derived apolipoprotein B alleles. Carriers of hypercholesterolemia in one family consistently under-expressed the form of apolipoprotein, which derived from inheritance of a particular apolipoprotein B gene, as a percentage of total serum LDL In non-carriers, this protein usually accounted for 33% of the total LDL protein but in six out of seven carriers this level was reduced to less than 15%. Thus, a variation in a gene's sequence, which is not in itself pathogenic, may have a role in an individual's susceptibility to a disease. Ultimate expression or lack of expression of a disease state will also depend on other genetic and environmental factors.

leles of a given sequence has expanded greatly with the recent technical advances in denaturing gradient gel electrophoresis, chemical cleavage, and single-stranded conformational electrophoresis. One would predict that information derived from the human genome project will have a major impact upon the isolation of further disease genes. As whole regions of human chromosomes or indeed entire chromosomes are physically m a p p e d and cloned as continuous, overlapping YACs (yeast artificial chromosomes), isolation of disease genes will become easier and easier. The major challenge now lies not in the elucidation of the large number of single-gene disorders, but in the effort to find major genes involved in c o m m o n diseases and congenital malformations and to sort out the different alleles of these genes. We look to the time, hopefully within 50 years, when most of the myriad disorders and congenital malformation syndromes seen in the genetics clinics of teaching hospitals can be accurately diagnosed by molecular methods. Prevention of recurrence of these disorders in subsequent offspring along with rational therapy should follow after their description in molecular terms.

Annotated references and recommended reading • •.

VANCEJM, NICHOLSON GA, YAMAOKALH, STAJICHJ, STEWART CS, SPEER MC, HUNG WY, ROSES AD, BARKERD, PERICAK-VANCE 1V~ Linkage of Charcot-Marie-Tooth n e u r o p a t h y type l a to c h r o m o s o m e 17. Exp Neurol 1989, 104:186~189. The first report linking a form of CMT disease to a locus on chromosome 17. This accounted for the failure to link some cases of CMT disease to the previously known locus o n chromosome 1. 1. "•


MCALPINEPJ, FEASBY TE, HAHN AF, KOMARNICmL, JAMES S, GUY C, DIXON M, QAYYUMS, WRIGHT J, COOPIAND G, LEWIS M, KA1TAH, PHILIPPS S, WONG P, KOOPMANW, COX DW, gEE WC: Localization of a locus for Charcot-Marie-Tooth neuropathy type l a (CMT1A) to c h r o m o s o m e 17. Genomics 1990, 7:408415.


MIDDLETON-PRICEHR, HARDING AE, MONTEmO C, BERCIANOJ, MALCOLMS: Linkage of hereditary m o t o r and sensory neuropathy type 1 to t h e pericentromeric region of c h r o m o s o m e 17. Am J H u m Genet 1990, 46:92-94.

Summary The pace of localization and characterization of genes affected in human genetic disorders is quickening. Many important genes were localized or characterized recently: genes for in cystic fibrosis, NF-2, Marfan's syndrome and xeroderma pigmentosum, to name a few. Also, in the past 15 months, the CFTR gene affected in cystic fibrosis has been isolated, the first disease gene to be isolated without use of previous cytogenetic clues, such as deletions or translocations in sporadic cases. Other examples should follow, although we have been disappointed to date by tile difficulties encour~tered in the isolation of Huntington's disease gene which was localized a number of years ago to distal chromosome 4p [54]. It is still very difficult to isolate a disease gene without critical cytogenetic information. New improved techniques for finding the desired expressed sequences in a large cloned segment of human DNA are needed. Our ability to find mutant at-

Of interest Of outstanding interest

BRZUSTOWICZLM, LEHNER T, CASTILLALH, PENCHASZADEHGK, WILHELMSENKC, DANIELS R, DAVIES KE, LEPPERT M, ZITER F, WOOD D, DUBOWlTZV, ZERRES K, HAUSMANOWA-PERTRUSEWlCZ I, OTr J, MUNSATTL, GILLIAMTC: Genetic mapping of chronic childhood-onset spinal muscular atrophy to c h r o m o s o m e 5q11.2-13.3. Nature 1990, 344:540-541. See [ 5 " ] . 4. •"

5. ••

MELKI J, ABDELHAK S, SHETH P, BACHELOT ME, BURLET P, MARCADETA, AICARDI J, BAROIS A, ARRIERE JP, FARDEAU M, FONTAN D, PONSOT G, BILLETT T, ANGELINI C, BARBOSA C, FERRIERE G, LANZI G, OTrOLINI A, BABRON MC, COHEN D, HANAUER A, CLERGET-DARPOUX F, LATHROP M, MUNNICH A, FREZALJ: Gene for chronic proximal spinal muscular atrophies m a p s to c h r o m o s o m e 5q. Nature 1990, 344:767-768. These two groups [4"•,5 ••] demonstrated a strong linkage between the disease locus for spinal muscular atrophy (types lI and III) and chromosome 5q.

The molecular basis of genetic disease Boehm and Kazazian 6.

GELIAM TC, BRZUSTOWlCZ LM, CASTILLA LH, LEHNER T, PENCHASZADEHGK, DANIELS RJ, BYTH BC, KNOWLESJ, HISLOP JE, SHAPIRAY, DUBOWITZ V, MUNSAT TL, OTT J, DAVIES KE: Genetic h o m o g e n e i t y b e t w e e n acute and chronic forms of spinal m u s c u l a r atrophy. Nature 1990, 345:823~325. A report showing that the disease locus for spinal muscular atrophy type I (like types II and Ill) is also linked to chromosome 5q. ,

KNOWLTONRG, KATZENSTEINPL, MOSKOWITZ RW, WEAVER EJ, MALEMUDCJ, PATHRIAMN, JIMENEZ SA, PROCKOP DJ: Genetic linkage of a polymorphism in t h e type II procollagen g e n e (COL2A1) to primary osteoarthritis associated w i t h mild chondrodysplasia. N Engl J Med 1990, 322:526-530. Although this report shows that inheritance of primary osteoatthritis in one large family is linked to the gene COI2A1, it does not show that the disease is caused by a defect in this gene.

17. •"

KEREMB-S, ROMMENSJM, BUCHANANJA, MARKIEWICZD, Cox TK, CHAKRAVART1A, BUCHWALDM, TsuI L-C: Identification of t h e cystic fibrosis gene. Gene Anal Sci 1989, 245:1073-1079. These three papers [15"',16",17 "°] describe the cloning of the gene responsible for cystic fibrosis. 18.

7. •


CHAMBERLAINS, SHAW J, ROWLAND A, WALLIS J, SOUTH S, NAKAMURAY, YON GABALNA, FAREALLM, WILLIAMSONPc Mapping of m u t a t i o n causing Friedreich's ataxia to h u m a n chrom o s o m e 9. Nature 1988 334:248-250.

9. •

CHAMBERLAIN S, SHAWJ, WALLISJ, ROWLANDA, CHOW L, FAREAL M, KEATS B, RICHTER A, ROY M, MELANCON S, DEUFEL T, BERCIANO J, WILI/AMSON Pc Genetic h o m o g e n e i t y at t h e Friedreich ataxia locus on c h r o m o s o m e 9. A m J H u m Genet 1989, 44:518-521. Despite the clinical beterogeneity of this disease it is almost always due to a gene, or set of genes, near the centromere of chromosome 9. 10.

MUSARELLAMA, WELEBER RG, MURPHEY WI-I, YOUNG RSL, ANSTON-CARTWRIGHTL, METS M, KRAFTSP, POLEMENOR, LITF M, WORTON RG: Assignment of t h e g e n e for complete X-linked congenital stationary night blindness (CSNB1) to X p l l . 3 . Genomics 1989, 5:727-737.

CUTTINGGR, KASCH LM, ROSENSTEIN BJ, ZIELENSKIJ, TsuI L-C, ANTONARAV3SSE, KAZAZ~N HH JR: A cluster of cystic fibrosis mutations in t h e first nucleotide-binding fold of t h e cystic fibrosis c o n d u c t a n c e regulator protein. Nature 1990, 346:366-369.


DRUMMML, POPE HA, CLIFFWH, ROMMENSJM, MARVINSA, TSUI L-C, COLLINS FS, FRIZZELLRA, WILSON JM: Correction of t h e cystic fibrosis defect in vitro by retrovirus mediated gene transfer. Cell 1990, 62:1227-1233. See [ 2 0 " ] . • "

20. ""

RICH DP, ANDERSON MP, GREGORY RJ, CHENG SH, PAUL S, JEFFERSON DM, MCCANN JD, KLINGER Iq~, SMITH AE, WELSH MJ: Expression of cystic fibrosis t r a n s m e m b r a n e conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 1990, 347:358-363. The first report from two groups [ 1 9 " , 2 0 " ] that expression of the cystic fibrosis gene in vitro corrects the defect in epithelial cells from patients with the disease. 21. •*

BARKER DF, HOSTIKKA SL, ZHOU J, CHOW LT, OLmHANT AR, GERKEN SC, GREGORY MC, SKOLNICK MH, ATIKIN CL, TRYGGVASON K: Identification o f mutations in t h e COL4A5 collagen gene in Alport syndrome. Science 1990, 248:1224-1226. See [24"] 22.

HOSTIKKASL, EDDY RE, BYERS MG, HOYHTYA M, SHOWS TB, TRYGGVASON K: Identification of a distinct type IV collagen a chain with restricted kidney distribution and assignment of its g e n e to t h e locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci USA 1990, 87:1606-1610. See [24"]. •

11. •

MCCAR~I-IYTV, HEALYJMS, HEFFRON JJA, LEHANE M, DEUFEL T, LEHMANN-HORNF, FAREALLM, JOHNSON K: Localization of t h e malignant hyperthermia susceptibility locus to h u m a n c h r o m o s o m e 19q12-13.2. Nature 1990, 343:562-563. The localization of the gene responsible for malignant hyperthermia to this site may implicate the gene for the skeletal muscle ryanodine receptor in this disorder, as it has also been localized to chromosome 19 cen~ll3.2. 12.

MACLEr,~NANDH, DUFF C, ZORZATO F, FUJI/ J, PH/ILIPS M, KORNELUK RG, FRODIS W, BRITT BA, WORTON RG: Ryanodine receptor g e n e is a candidate for predisposition to malignant hyperthermia. Nature 342:559-561.

13. •"

HASTBACKAJ, KAITILAI, SISTONEN P, DE LA CHAPELLEAA Diatrophic dysplasia g e n e m a p s to t h e distal long arm of chrom o s o m e 5. Proc Natl Acad Sci USA 1990, 87:8056-8059. This region of c h r o m o s o m e 5 includes several genes for growth factors, growth factor receptors and hormones which may have a role in this disease. COSTAFF, AGRE P, WATIONSPC, WINKELMANJC, TANG TK, JOHN KM, Lux SE, FORGET BG: Linkage of dominant hereditary spherocytosis to t h e gene for t h e erythrocyte m e m b r a n e skeleton p r o t e i n ankyrin. N E n g l J M e d 1990, 323:1046-1050. In a large family, no crossing over was found between hereditary spherocytosis and the ankyrin gene.


MYERSJC, JONES TA, POHJOLAINENE-R, KADRIAS, GODDARDaD, SHEER D , SOLOMON E, PIHLAJANIEMI T: Molecular cloning of a5(IV) collagen and assignment of t h e gene to t h e region of t h e X c h r o m o s o m e containing the Alport syndrome locus. A m J H u m Genet 1990, 46:1024=1033. See [24"]. t


FLINTERFA, ABBS S, BOBROWM: Localization of t h e g e n e for classic Alport syndrome. Genomics 1989, 4:335-338. The above four papers [21°%22"-24 "] describe the association between three distinct mutations in the collagen gene COL4A5 and Alport syndrome in three families. 25. ""



15. •"

ROMMENSJM, IANNUZZIMC, KEREMB-S, DRUMMML, MELMERG, DEANM, ROZMAHELR, COLE JL, KENNEDY D, HIDAKAN, ZSIGA M, BUCHWALDM, RIORDANJR, TSUI L-C, COLLINSFS: Identification of t h e cystic fibrosis gene: c h r o m o s o m e s walking and jumping. Science 1989, 245:1059-1065. See [17"']. 16. "*

RIORDANJR, ROMMENSJM, KEREM B-S, ALON N, ROZMAHEI R, GRZELCZAKZ, ZIELENSKIJ, LOK S, PIAVSIC N, CHOU J-L, DRUMM ML, IANNUZZaMC, COLLINS FS, TSUI L-C: Identification of t h e cystic fibrosis gene: cloning and characterization of complementary DN& Science 1989, 245:1066-1073. See [17"'].


CALLKM, GLASERT, ITO CY, BUCKLERAJ, PELLETIERJ, HABERDA, ROSEEA, KRALA, YEGER H, LEWISWH, JONES C, HOUSMANDE: Isolation and characterization of a zinc finger polypeptide g e n e at t h e h u m a n c h r o m o s o m e 11 Wilms' t u m o r locus. Cell 1990, 60:509-520.


26. "

GESSLERM, POUSTKAA, CAVENEEW, NEVE RL, OP,K~ SH, BRUNS GAP: Homozygous deletion in Wilms t u m o u r s of a zinc-finger g e n e identified by c h r o m o s o m e jumping. Nature 1990, 343:774-778. The above two papers [25°%26 ' ' ] report the isolation of a candidate gene for Wilms' tumour. It encodes a zinc-finger protein which is likely to be a transcription factor. 27. •

PRITCHARD-JONESK, FLEMING S, DAVIDSON D, BICKMORE W, PORTEOUSD, GOSDEN C, BARD J, BUCKLER A, PELLETIERJ, HOUSMAN D, VAN lq~YNINGEN V, HASTIE N: T h e candidate Wilms's t u m o u r g e n e is involved in genitourinary development. Nature 1990, 346:194-197. See [28*] 28. ,




Mammalian gene studies an l l p 1 3 zinc finger g e n e contributes to t h e d e v e l o p m e n t of Wilms' tumor. Cell 1990, 61:1257-1269. A 2 5 b p deletion in the candidate gene described above [27%28.] is found in a Wilms tumor, but not in the patient's germline DNA. This is consistent with inactivation of a tumor suppressor gene. 29. *"

VISKOCHILD, BUCHBERG AM, Xo G, CAWTHON RM, STEVENS J, WOLFF RK, CULVER M, CAREY JC, COPEI~ND NG, JENKINS NA, WHITE R, O'CONNELL P: Deletions and a translocation interrupt a cloned g e n e at t h e neurofihromatosis type 1 locus. Cell 1990, 62:187-192. See [32 °. ] 30. ""

WALLACEMR, DOUGLAS MA, ANDERSEN LB, LETCHER R, ODEH HM, SAUL1NOAM, FOUNTAINJW, BRERETON A, NICHOLSON J, MYrCHELLAL, BROWNSTEINBH, COLLINSFS: Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990, 249:181-186. See [32"*] 31. ''

CAWTHONRM, WEISS R, XU G, VISKOCHILD, CULVERM, STEVENS J, ROBERTSONM, GESTELANDR, DUNN D, O'CONNELL P, WHITE R: A major s e g m e n t o f the neurofibromatosis type 1 gene: cDNA sequence, g e n o m i c structure and point mutations. Cell 1990, 62;193-201. See [ 3 2 " ] 32. ""

Xu G, O'CONNELLP, VISKOCHILD, CAWTHONR, ROBERTSONM, CULVERM, DUNN D, STEVENSJ, GESTELANDR, WHITE R, WEISS R: T h e neurofibromatosis type 1 gene e n c o d e s a protein related to GAP. Cell 1990, 62:599-608. The above four papers [ 2 9 " - 3 2 " ] describe the isolation of the gene responsible for NF-1. Various mutations within the gene have been associated with disease. The encoded protein shows significant homology with mammalian cytoplasmic GAP proteins. 33. *

JARCHOJA, MCKENNA W, PARE PJA, SOLOMON SD, HOLCOMBE RF, DICKIE S, LEVIT, DONIS-KELLERH, SEIDMANJG, SEIDMANCE: Mapping a g e n e for familial hypertrophic cardiomyopathy to c h r o m o s o m e 14q. N EngIJ Med 1989, 321:1372 1378. One large kindred with hypertrophic cardiomyopathy showed very tight linkage to the chromosome 14ql. Because of its similar location, the gene encoding 13 cardiac myosin heavy chain is a possible candidate gene for the disease. 34. ""

TANIGAWAG, JARCHO JA, KASS S, SOLOMON SD, VOSBERG I-L P, SEIDMANJG, SEIDMAN CE: A molecular basis for familial hypertrophic cardiomyopathy: an cc/13 cardiac myosin heavy chain hybrid gene. Cell 1990,62:991-998. In this family with hypertrophic myopathy, the disease was caused by a hybrid gene of the c~/[3 cardiac myosin heavy chain. 35.

OZAWAT, TANAKAM, SUG1YAMAS, ITATTOPd K, Iwo T, OHNO K, TAKAHASHIA, SATO W, TAKADAG, MAYUMI B, YAMAMOTO K, ADACHI K, KOGA Y, TOSHIMA H: Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients w i t h hypertrophic or dilated cardiomyopathy. Biocbem Biopbys Res Commun 1990, 170:830-836.

36. ,

LEE B, VISSING H, RAMIREZF, ROGERS D, RIMOIN D: ldentification o f t h e molecular defect in a family with spondyloepiphyseal dysplasi,'L Science 1989, 244:978-980. In several cases, this disease results from mutations within the COL2A1 collagen gene. These include a 390 bp deletion of exon 48 which leaves the reading frame intact. 37.

TILLERGE, RIMOIN DL, MURRAYLW, COHN DH: T a n d e m duplication within a type II collagen g e n e (COL2AI) e x o n in an individual w i t h spondyloepiphyseal dysplasia. Proc Natl Acad Sci USA 1990, 87:3889-3893.


MURRAYLW, BAUTISTAJ, JAMES PL, RIMOIN DL: Type II collag e n defects in t h e chondrodysplasias I spondyloepiphyseal dysplasia. A m J H u m Genet 1989, 45:5-15.




by ERCC-3 is involved in t h e h u m a n repair disorders xerod e r m a p i g m e n t o s u m and Cockayne's syndrome. Cell 1990, 62:777-791. The microinjection of mRNA encoding the ERCC-3 protein corrected the DNA repair defect in cells from a patient with xeroderma pigrnentosum in vitro. 40.

KAINULAINENK, PULKKINENL, SALOLAINENA, KAITILAI, PELTONEN L: Location o n c h r o m o s o m e 15 of the g e n e defect causing Marfan syndrome. N Engl J Med 1990, 323:935-939. The locus for disease has been linked to chromosome 15q in five out of five informative pedigrees. .

41. .

HOtEISTERDW, GODFREY M, SAKAI LY, PYERITZ RE: I m m u n o histologic abnormalities of t h e microfibrillar-fiber system in the Marfan syndrome. N E n g l J Med 1990, 323:152-159. This study implicates a defect in the fibrillin gene in this disease although the chromosomal location is not yet known. 42.

NICHOLLSRD, KNOLL JHM, BUTTER MG, KARAM S, LALANDE M: Genetic imprinting suggested by maternal heterodiso m y in non-deletion Prader-Willi syndrome. Nature 1989, 342:281-285. Two cases of non-deletion Prader-Willi syndrome which were associated with the inheritance of both copies of the mammal chromosome 15 and no copies of the paternal homologue. This supports the hypothesis that the gene responsible has different functions on the paternaUy and maternally derived chromosome 15. ,

43. .

WALLISGA, STARMANBJ, ZINN AB, BYERS PH: Variable expression of osteogenesis imperfecta in a nuclear family is explained by somatic mosalcism for a lethal point mutation in t h e aI (1) gene (COL1A1) of type 1 collagen in a parent. Am J H u m Genet 1990, 46:1034-1040. The survival of a father with a lethal point mutation for this disease (which killed his son perinatally) was shown to be the result of somatic mosaicism. Only a portion of his cells contained the mutation which had arisen during embroyogenesis. 44.

ZEVlANI M, SERVlDEI S, GELLERA C, BERTINI E, DIMAURO S, DIDONATO S: An autosomal dominant disorder w i t h multiple deletions o f mitochondrial DNA starting at the D-loop region. Nature 1989, 339:309--311. This study suggests that a mutation within nuclear DNA, which is inherited as an autosomal dominant trait, can promote de novo deletions within mitochondrial DNA. .

45. .

ACClLt D, FRAPIER C, MOSTHAF L, MCKEON C, ELBEIN SC, PERMUTFMA, RAMOS E, LANDER E, ULLRICHA, TAYLOR SL: A mutation in t h e insulin r e c e p t o r gene that impairs transport of t h e r e c e p t o r to the plasma m e m b r a n e and causes insulin-resistant diabetes. EMBO J 1989, 8:2509-2518. See [46"]

46. .

KLINKHAMERMP, GOREN NA, VAN DER ZON GCM, LINDHOUTD, SANDKUYL LA, KRANSHMJ, MOLLERW, MAASSENJ& A leucineto-proline m u t a t i o n in t h e insulin receptor in a family w i t h insulin resistance. EMBO J 1989, 8:2503-2507. The two papers above [45", 46"] demonstrate the principle that different genetic diseases can be produced by different mutations in the same gene. 47.

ERANCOMANOCA, LIEBERFARB RM. HmOSE T, MAUMENEE I, STREETEN EA, MEYERSDA, PYERITZRE: T h e Stickler syndrome: evidence for close linkage to t h e structural g e n e for type II collagen. Genomics 1987 1:293-296.


Hu X, BURGHES AHM, BULMANDE, RAY PN, WORTON RG: Evid e n c e for mutation by u n e q u a l sister chromatid e x c h a n g e s in t h e D u c h e n n e muscular dystrophy gene. Am J H u m Genet 1989, 44:855-4363.


SEBOUNE, ROBINSON/VIA, DOOLITI'LE TH, ClUtLA TA, KINDT TJ, HAUSER SL: A susceptibility locus for multiple sclerosis is linked to t h e T cell receptor 13 chain complex. Cell 1989, 57:1095--1100.


ARDINGERI-IH, BUETOW KH, BELL GI, BARDACHJ, VANDENMARK DR, MURRAYJC: Association of genetic variation of t h e trans-

The molecular basis of genetic disease B o e h m a n d Kazazian forming growth factor-alpha gene with cleft lip and palate.


GAVISH D, BRINTON EA, BRESLOWJL: Heritable aUele-specific differences in amounts of apoB and low-density lipoproreins in plasma. Science 1989, 244:72-76.



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HERBERTPN, ASSMANNG, GOTrO AM JR, FREDRICKSONDS: In The metabolic basis of inherited disease edited by Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MD. New York: McGraw-Hill, 1983, 5, pp 589-651. BROWNMS, GOLDSTEINJL: A receptor-mediated pathway for cholesterol homeostasis. Science 1986, 232:34-47


The molecular basis of genetic disease.

The pace of localization and characterization of genes affected in human genetic disorders is quickening. Many important genes were localized or chara...
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