Genetic linkage studies of human neurodegenerative disorders Rudolph E. Tanzi Massachusetts

General Hospital,

Charlestown,

Massachusetts,

USA

Recombinant DNA technology has the ability to delineate the causes of several neurodegenerative disorders. Genetic linkage studies have been used successfully to localize gene defects and it is likely that in the near future the exact loci will be determined.

Current

Opinion

in Neurobiology

Introduction Over the past decade, the recognition

that DNA polymorphisms, ubiquitously distributed throughout the human genome, can be employed as genetic markers has provided a powerful means of investigating inherited neurological disorders for which no protein defect is known. DNA polymorphisms appear in various forms ranging from restriction fragment length polymorphisms to highly informative multiple nucleotide repeat sequences. This allows both genes and anonymous DNA fragments to be tested for linkage to gene defects. Once the chromosomal location of a genetic defect is determined, a disease gene can then be isolated and its product identified and characterized. Genetic linkage analysis has been used successfully to localize gene defects for familial Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, This review will discuss the progress and problems encountered in the ongoing efforts to pinpoint the gene defects for these three neurodegenerative disorders. Aizheimer’s

disease

Alzheimer’s disease is a neurodegenerative disorder of the central nervous system characterized by major deficits in cognitive function. The neuropathological profile of the disease includes the formation of insoluble proteinaceous fibers. Extracellularly, j3A4amyloid in the form of senile plaques and cerebral blood vessel deposits is observed, while neurofibrillary tangles accumulate, inside neurons [ 1,2]. Alzheimer’s disease is generally considered to be a sporadic disorder, but increased risk of onset has been reported in relatives of Alzheimer patients [3,4*,5]. In-cases of familial clustering of Alzheimer’s disease, the disorder segregates in an autosomal dominant fashion and is referred to as familial Alzheimer’s disease (FAD). It is often difficult to assess whether familial aggregation of Alzheimer’s disease reflects genetic inheritance

1991, 1:455-461

or simply clustering of sporadi&Jzheimer’s disease as a result of environmental factors or ascertainment bias. Consequently, considerable controversy surrounds the issue of what proportion of Alzheimer’s disease is familial, with estimates ranging from 5% to 100% [3,5]. Although the largest FAD kindreds involve an early age of onset (40-50 years), FAD is otherwise neuropathologically and clinically identical to the sporadic cases. Genetic studies of familial

Alzheimer’s

disease

Initial efforts to localize the FAD gene defect concentrated on chromosome 21 based on the observation of numerous senile plaques and neurofibrillary tangles in the brains of older patients with Down syndrome (trisomy 21) [2,6]. In 1987, a putative FAD gene defect was discovered to be genetically linked to DNA markers on the proximal long arm of chromosome 21 in four large FAD pedigrees with early age of onset ( < 65 years) [7]. At that same time, the gene encoding the precursor protein of the major component of Alzheimer’s disease-associated amyloid, the 42-amino-acid peptide j3A4, was isolated and mapped to this same general region of chromosome 21 [8-111. The later observation of several recombination events between the amyloid precursor protein (APP) and FAD, however, suggested that APP was not the site of the primary FAD gene defect [ 12,131. Several laboratories subsequently tested additional FAD

kindreds for linkage to chromosome 21. Tkvo groups obtained additional evidence supporting the presence of an FAD gene defect in the centromeric portion of chromosome 21 [ 14,151. Meanwhile, other groups suggested the possibility of non-allelic genetic heterogeneity based on the exclusion of FAD from chromosome 21 DNA markers in various pedigrees [16,17]. Signiticant evidence for non-allelic genetic heterogeneity of FAD has been obtamed via an intensive international collaboration [ 18**] in which 48 pedigrees have been tested for linkage to markers from the proximal portion of chromosome 21.

Abbreviations AIS-amyotrophic lateral sclerosis; APP-amyloid precursor protein; FAD-familial Alzheimel’s disease; HCHWA-D-hereditary cerebral hemorrhage with amyloidosis-Dutch type; H&Huntington’s disease. @ Current Biology Ltd ISSN 0959-43Bfl

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Disease, transplantation and regeneration The total data set yielded sign&ant evidence for linkage of FAD to the chromosome 21 loci D21U/D2ISII, D21S13/D21SlG, and D21S52. In addition, the ‘affected pedigree member’ method [ 191, which examines the frequency with which affected family members share alleles of a specific polymorphism, confirmed the results by demonstrating a signiIicant degree of association between FAD and chromosome 2 1. The data obtained in this study revealed that only a subset of pedigrees contributed positively to the overall linkage results. Basically, combined pedigrees exhibiting an early age of onset ( < 65 years) displayed positive linkage with chromosome 21, while kindreds manifesting a late age of onset were unlinked. Attempts to determine the exact location of the early onset FAD gene defect by multipoint analysis yielded peaks in two distinct regions of chromosome 21, one in the centromeric portion and the other distal to the locus D21Sl/D21Sll, near the APP gene. The presence of two separate peaks could be explained by either two different FAD loci on chromosome 21, or the existence of non-allellc genetic heterogeneity within the set of early onset pedigrees, in which case recombination events derivingfrom unlinked pedigrees would confound the localization of the FAD gene defect in the chromosome 21 -linked pedigrees. With the establishment of genetic heterogeneity in FAD, the human genome was further scanned for additional FAD loci. For this purpose, Perk&-Vance and colleagues [20*] examined 32 pedigrees (29 late onset and three early onset). In this study, the affected pedigree member method was employed to remove the effects of una&ted at risk individuals from the analysis, and so that no assumptions would have to be made about modes of inheritance. The analysis indicated an overall positive association of FAD with chromosome 19. Standard genetic linkage (maximum likelihood) analysis, however, incorporating age of onset information provided no evidence of FAD linkage to chromosome 19. When maximum likelihood analysis was performed using only affected individuals, positive evidence of genetic linkage was obtained. The discrepant results obtained with these methods suggest at least three possibilities: first, that the age-of-onset curve employed was not completely accurate so that the inclusion of unaifected at risk individuals skewed the analysis; second, that the gene defect on chromosome 19 involves susceptibility rather than causation; and third, that linkage of FAD to chromosome 19 represents a false positive result. All of the kindreds tested in the above study manifested a late age of onset ( > 65 years). This same set of pedigrees also yielded evidence of linkage to chromosome 21. Three early onset pedigrees in the study, however, displayed positive linkage solely to chromosome 21. These results agree with the collaborative study of St. George-Hyslop [18**], and another study by Schell enberg and colleagues [ 211, in which only early onset pedigrees provided evidence of linkage to chromosome 21. In a study of 59 FAD pedigrees (mixed early and late age of onset) with markers from both chromosomes 19 and 21, the combined results excluded tight genetic link-

age to all loci tested. Only the two chromosome 21 loci, D21Sl/D21Sll and D21S13/D21SlG yielded evidence suggestive of linkage [22]. Once again, as a group, the early age of onset FAD families provided significant evidence of linkage to chromosome 21, while late age of onset pedigrees were essentially negative with all loci tested except the single chromosome 19 locus, Ai’PlA.3, in which suggestive evidence of linkage was obtained only when the unaffected at risk individuals were dropped from the analysis. Collectively, these results show that FAD is not a homogeneous disorder. Inherited early age of onset and late age of onset Alzheimer’s disease clearly appear to involve different genes. Moreover, FAD kindreds exhibiting an early age of onset probably involve more than one gene defect, demonstrated, for example, by the lack of linkage of early onset Volga German pedigrees to chromosome 21 [ 21 I. FAD loci appear to map to both chromosome 19 and 21, although the modes of inheritance of these gene defects and their modus operandi (causation or predisposition) may not be identical. The complex genetic picture of FAD depicted by the available data suggests that a virtual myriad of gene-to-gene and perhaps, gene-to-environment interactions are at play in this disorder and remain topics for future studies.

The role of amyloid precursor protein in familial Alzheimer’s disease A close scrutiny of the pathological features of an inherited disease can often lead to the identification of candidate genes for the site of the gene defect. Clearly, the major focus in studies of FAD has been the APP gene. APP resides on chromosome 21 immediately proximal to the obligate Down syndrome region at the border of bands 21q21.3 and 21q22 [ 231, suggesting that the presence of amyloid deposits in the brains of patients with Down syndrome are most likely the result of gene dosage. With the exception of one apparently premature report [24], however, increased APP gene dosage at the germllne level does not appear to account for the presence of amyloid in Alzheimer’s disease or FAD [ 25271. Although the APP gene was originally excluded from genetic linkage to FAD in several pedigrees [ 12,131, the recent establishment of non-allelic genetic heterogeneity has raised the possibility that APP might still be the site of the defect in some FAD pedigrees. Along these lines, Goate et al. [28**] have examined APP genetic linkage in several FAD families and obtained preliminaty evidence suggestive of linkage in two pedigrees revealing no crossovers with APP. This group then proceeded to sequence and find a missense mutation in exon 17 of the APP gene in affected individuals from both pedigrees. Exon 17 was initially chosen on the basis of the recent discovery that a mutation in this exon (encoding the carboxy-terminal portion of j3A4) at residue 693 (APP693 mutation, Fig. 1) is the gene defect in the rare disorder, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) [29*]. In HCI-IWA-D, j3~4-rype amy-

Genetic

loid accumulates in large amounts in cerebral vessels and ultimately leads to stroke and death by the fifth or sixth decade of life [30]. The single-base substitution found by Goate et al. [28**] causes the conservative substitution of an Ile for a Val at residue 717 (AP~717 mutation) within the transmembrane region immediately carboxy-terminal to the PA4 domain (Fig. 1). This base substitution co-segregated perfectly with FAD in two separate pedigrees tested by Goate and colleagues but was absent in several other families and 100 control individuals. More recently, its appearance in four additional pedigrees [31*,32**] and absence in the vast majority of early and late onset FAD pedigrees tested [ 28-310,32**,33*], lends considerable support to the hypothesis that this single base substimtion represents a rare mutation. Interestingly, affected members of families reported to contain the APP717 mutation manifest a peculiar neuropathological proiile characterized by cortical diifuse Lewy bodies and abundant congophylic amyloid angiopathy, leading in some cases to stroke [28**,31*,32**]. This latter feature is highly reminiscent of the phenotype of patients with HCHWA-D in which dementia is sometimes observed to follow the onset of cerebral strokes [34], and suggests the possibility that the two known APP mutations, APP693 and APP717, may actually represent al lelic variants of a disorder marked by prominent cerebrovascular amyloidopathy and stroke. The role played by the APP717 mutation in Alzheimer’s disease neuropathogenesis is not yet clear. At the protein level, the larger non-polar side chain of Ile (relative to that of Val) may disrupt membrane integrity. A precedent for this possibility exists in the C. eleguns muta tions degl(u38) and mec4 in which late onset neuronal degeneration results from the replacement of an Ala residue in the hydrophobic membrane spanning domain with amino acids containing larger side arm groups (e.g. Thr [35,36]). Likewise, the larger side chain on Ile versus Val at APP693 may ultimately lead to late onset neuronal membrane degeneration. As a consequence, uncleaved, ful-length APP molecules containing intact PA4 domains

linkage studies

of human

neurodegenerative

disorders

Tanzi

might then escape into the extracellular space, perhaps leading to aggregation of PA4 and amyloid formation. Why this should predominantly result in the generation of vessel amyloid, however, is unclear. An alternative possibility for the mechanism of APP717 mutation involves the ensuing disruption of a putative regulatory stem-loop structure [37**]. The stem-loop occurs precisely at position 40 of the PA4 domain and resembles the iron-responsive elements in the ferritin and transferrin receptor RNAS. In these RNAs, the ironresponsive elements regulate translation in response to iron concentration. The mutation at ~~~693 destabilizes the stem of the putative iron-responsive element in APP, perhaps leading to alterations in translation (e.g. amount of protein produced, or production of truncated prod ucts) and ultimately to accelerated amyloid formation. The extent to which mutations in the A& gene underlie FAD remains to be determined -@:W&W of the genetic linkage results, it is [email protected]&whether link age of FAD to chromosome 21 &i-r be entirely explained by mutations in APP. The largest and most informative FAD pedigree tested by St. George-Hyslop and colleagues [7,18**] yielded a single peak LOD-score of 2.94 at 15 CM with the chromosome 21 marker D21S52, which resides approximately 15 CM from APP. In this early onset FAD kindred of Italian origin, two different APP alleles appeared to segregate with Alzheimer’s disease in two separate branches of the pedigree. Given the high improbability that all affected individuals in each branch were mistyped or misdiagnosed in the same way, the obligate crossover event between FAD and APP implies that either APP is not the site of the defect in this family, which otherwise provides highly suggestive but not quite significant linkage to chromosome 21, or APP does actually contain the gene defect, and the crossover represents an intragenic recombination event within the APP gene, or is due to the introduction of a second FAD gene defect into the kindred. Sequencing of the APP gene in affected individuals of this pedigree should resolve the issue. Highly informative polymorphisms immediately flanking APP can be used to Fig. 1. The amyloid precursor protein (APP) molecule and the sites of mutations found in the portion encoded by exon 17. A signal peptide is removed upon insertion into the membrane. Two extracellular domains encoded by alternatively-spliced exons include the Kunitz protease inhibitor (KPI) and the OX-2 like region (II). Alternatively, the APP molecule may be integrated into intracellular membranes as opposed to plasma membrane. The mutations, APP693 and APP717 represent proposed defective sites for hereditary cerebral hemorrhage with amyloidosisDutch type (HCHWA-D) and an inherited form of familial Alzheimer’s disease (FAD) involving the presence of diffuse Lewy bodies and excessive cerebrovascular amyloid, respectively.

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decipher the genetics of the family and address the possibility of intragenic recombination. For now, the existing genetic linkage results obtained with this pedigree continue to support the possibility of a second FAD locus on chromosome 21. AS this pedigree reveals more classic Alzheimer’s disease pathology (devoid of events of cerebral hemorrhage and stroke and diffuse Iewy bodies), further genetic linkage analysis of this kindred could possibly lead to the identification of a more universal FAD defect on chromosome 21 or elsewhere in the genome. Huntington’s

disease

Huntington’s disease (HD) is an autosomal dominant disorder of the central nervous system characterized by adult onset (35-42 years> of progressive involuntary movement and dementia [38]. The biochemical basis for the premature selective striatal neuronal loss and symptoms of HD are unknown. The prevalence of HD is approximately 1 in 10 000 [39]. Unlike Alzheimer’s disease, HD is completely penetrant, meaning that carriers of the gene defect will invariably show symptoms of the disorder in the period of a normal lifespan. Over the past decade, HD has emerged as the classic neurological disorder of unknown etiology for which recombinant DNA technology holds the power to delineate the cause. In 1983, a DNA marker, G8, mapping to the short arm of human chromosome 4 (4p16.3), was genetically linked to HD [ 401, representing the first instance in which a genetic defect had been mapped solely by DNA marker link age analysis, and setting the stage for similar studies in multiple disorders. Subsequently, the search for the I-ID gene has aptly Illustrated both the progress and obstacles encountered in carrying out ‘location cloning’ strategies. Following the initial discovery of linkage, HD was shown to be genetically homogeneous [41] indicating that linkage results from virtually all HD families studied could be pooled for the purpose of finely localizing the gene defect. Early multipoint analyses calculated with data obtained from multiple HD kindreds indicated that HD mapped distal to the G8 locus, to D4SIO in band 4~16.3. This conhned the search for the HD gene defect to the approximately 6 million basepairs of DNA bounded by D4SlO and the telomere. A large collaborative effort involving multiple groups and organized by the Hereditary Disease Foundation combined resources to produce large numbers of probes from 4~16.3 and to physically map them. One result was the construction of a pulse-field, gel electrophoresis-generated, long-range restriction map covering 5.5 million basepairs between D4SlO and the telomere [42]. Two unmapped gaps in this span separated the region into three major clusters. In general, this region was found to contain a relatively high density of ‘rare-cutter’ restriction sites indicating the presence of coding DNA The major task with regard to isolating the HD gene is to now determine which cluster in this region contains the defect. In the absence of any physical rearrangements in the candidate region, HD families have thus far had to be analyzed and recombination events identified for use as landmarks.

These can then be employed to target the interval containing the HD defect. Several families have been found to display crossovers between D4SlO and I-ID, but a genetic linkage map of this region [43,44] has revealed that the frequency of recombination is not distributed evenly across the candidate region but concentrated immediately distal to D4SlO. A genetic distance of 6 CM between LMSlO and D4S90 occurs in an interval of only 200 000 basepairs Irnmediately distal to D4SZO [45*~]. Based on these iindings, one would predict that many crossovers observed between D4SZO and I-ID occur immediately distal to the former locus. Three of the identiiied crossovers are recognized by the multiple loci spanning the stretch between D4SlO and the telomere [43,46,47], positioning the HD gene in the terminal one million basepairs of 4p. One recombination event, however, observed in the large Venezuelan pedigree (used by Gusella, Wexler, and colleagues [40] to originally map HD), contradicts this position and suggests a location for the gene at a much more proximal location on 4p. These discrepant results can be explained by several possibilities: first, both locations may be correct in which case either one very large gene or two separate genes would be responsible for the disorder; second, one or more of the crossovers may be false, e.g. the result of misdiagnosis; and third, the one contradictory cross may represent a double-crossover event. Bates and colleagues [48*] have recently isolated a yeast artiiicial chromosome clone spanning the telomere of 4p resulting in a new marker D4SZ42. This locus is physically located 100 kb from the telomere of 4p and recognizes the three crossovers that suggest a distal location for HD. Based on this information, the three crossovers would place the HD defect in the distal 100 000 basepairs of 4p. This segment has been found to display no evidence of structural rearrangement between HD and normal chromosomes [48*,49*]. Before the true location of HD can be defined, it is critical to determine whether the three recombinants Indicating a telomeric position are single crossover events, or the result of misdiagnosis, double recombination, or even gene conversion. For this purpose, a marker at the telomere itself would need to be tested in the three recombinants. In addition, the sole Venezuelan recombinant pointing to a more proximal placement could be tested against a polymorphic telomeric marker to assess the possibility of a double crossover event. If one were detected in this individual, the I-ID gene could be unanimously pinpointed to the distal 100000 basepairs of 4p which have already been entirely cloned. For the present, however, the location of the HD gene must be divided into two regions, one just distal to D4SZ0, and the other in the last 100 kb of 4p. Amyotrophic

lateral sclerosis

Amyotrophic lateral sclerosis (AIS) is a progressive paralytic disorder caused by the degeneration of brain and spinal cord large motor neurons [50]. The etiology of

Genetic linkage studiesof human neurodegenerativedisorders Tanzi

AIS is unknown, but 5-10% of cases appear to be inherited in an autosomal dominant fashion with age-dependent penetrance. The prevalence of AIS in the USA is estimated to be approximately five or six in 100 000, therefore familial clustering is rare [ 511. Despite these odds, Siddique, Brown and colleagues [52-•] have managed to collect and investigate a large cadre of pedigrees and have recently reported genetic linkage of ALS to chromosome 21. Armed with 23 families exhibiting familial AIS, these investigators tested four DNA markers previously ordered on a genetic linkage map of chromosome 21 [ 531. Although, none of the four markers exhibited significant linkage to familial AIS in a two-point maximum likelihood analysis, multipoint analysis, incorporating the data of all four markers, yielded an LOD-score of 5.03 at the locus DZlS58 that maps 9 CM distal to APP. In this same study, significant evidence for genetic heterogeneity was obtained with a best estimate of 55% for the proportion of families with linkage to chromosome 21. These findings bear a curious resemblance to linkage of FAD to chromosome 21. In both disorders, the combined family results provide evidence of linkage to DNA markers in the vicinity of APP. In ALS, the peak LQDscore occurs just distal of APP, while in FAD, the overall peak occurs proximal to APP. Interestingly, in Guam Parkinsonian-dementia with AIS, neuropathological features of Alzheimer’s disease have been observed [ 541 including the observation of PA4 immunoreactivity associated with neurofibrillaty tangles. In addition, pedigrees exhibiting co-segregation of both familial AIS and FAD have been reported suggesting a possible genetic tie between the two disorders. The overall pairwise linkage to APP in the familial ALS study was mildly positive and obligate crossover events were observed in some families. Like FAD, these results could be explained by genetic heterogeneity in which unlinked pedigrees would confound the localization of the gene defect in linked kindreds. These similarities, in combination with the difficulties entailed in determining via genetic linkage analysis which families (FAD and familial AIS) contain defects on chromosome 21, suggest that it may be prudent to test both new and existing FAD and familial AIS families for linkage not only to more highly informative polymorphic markers (e.g. dinucleotide-repeats) from maximally-linked regions of chromosome 21, but also to highly informative polymorphisms at the APP locus.

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PERICAK-VANCE MA, YAMAKOALH, HAYNESCS, GASKEU PC, HUNGW-Y, CLARKCM, H!znw~ AL, ROSESAD: Genetic Linkage Studies in Alzheimer’s Disease Families. Exp Neural 1988, 102~271-279.

creates an amino acid change at position 693 of APP770 replacing a Glu with a Gln.

30.

18. ..

ST. GEORGE-HYSLOP PH ANDTHE FAD COUABORA~~~E GROUP: Genetic Linkage Studies Suggest that Alzheimer’s Disease is not a Single Homogeneous Disorder. Nature 1990, 347:194-197. Provides signilicant evidence for non-allelic genetic heterogeneity in FAD. Early and late age of onSet forms of FAD are shown to b=egenetically heterogeneous; the gene defect in some early- but no late-onset pedigrees is genetically linked to chromosome 21. 19. 20. .

WEEKS D, IANGEK: The mected Pedigree Member Method of Linkage Analysis. Am J Hum Genet 1988, 42~315326. PERICAK-VANCE MA, BEBOUT JL, GAXELL PC, YAMAOKALH, HUNGW-Y, AIBERTSMJ, WAUCERAP, B~~nem RJ, HAYNESCA, WELSHKA, ET AL: Linkage Studies in Familial Alzheimer’s

Disease: Evidence for Chromosome 19 Linkage. Am J Hum Genet 1991, 48:1034-1050. This paper provides evidence supporting a gene defect on chromosome 19 for late-onset FAD. Significant evidence of linkage requires the exclusion of at risk individuals from the analysis, indicating the potential involvement of a predisposing as opposed to a causative gene defect. 21.

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LUCOTIXG, BERRICHE S, DAVIDF: Alzheimer’s Mutation. Nufure 1931, 351:530. ieports the presence of the APP717 mutation in a family with inherited Alzheimer’s disease in which cerebral vessel amyioid is the prominent feature. Suggests that the ~~~693 and APP717 mutations are allelic wriants of a similar disorder. 31.

M-C, BROWNJ, GOAT A, HARDVJ, MULIANM, CHARTIER-HARUN R~%%R M, COLLINGE J, ROBERTS G: Molecular Classification of Alzheimer’s Disease. Lczncet1991, 337:1342-1343. Reviews several families with apparent inherited Alzheimer’s disease in which the APP717 mutation segregates. As these families present excessive cerebrovascular amyloid, stroke and hemorrhage, the authors suggest that the disease caused by this mutation is aCN@ ‘b-amyioidopathy’ as opposed to classic FAD. Provides more evidence that APP693 and APP717 may result in similar disorders. 32. ..

33. .

SCHELLENBERG GD, ANDERSONL, O’DAHL S, WISJMANEM, SAWVN~CKAD, BAU MJ, IAR.S~NEB, KUKU~L WA, MARTINGM, ROSESAD, ET AL: APP717, APP693 and PRIP Gene Mutations

are Rare in Alzheimer’s Disease Am J Hum Genet 1991, in press. Provides ample evidence that the ~~~693, APP717 and prion precursor protein mutations are extremeiy rare in FAD pedigrees. 34.

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DELABAR J-M, GOLDGABERD, IAMOURY, NICOLEA, HURETJ-L, DE GROUCHY J, BROWNP, GAJDUSEKDC, SINETPM: p Amyloid Gene Duplication in Alzheimer’s Disease and Karyotypically Normal Down Syndrome. Science 1987, 235:1390-1392.

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TANZI RE, HYMANBT: Alzheimer’s Mutation. Nature 1991, 37. .. 350:564. Proposes the hypothesis that the APP717 mutation disrupts a putative iron responsive-like stem loop structllre in APP RNA Based on the role of such StIUcNreS in other messengers (e.g. ferritin mRNA), it is proposed that the base change potentially deregulates or alters translation of APP.

26.

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POLIEN D, DRACHMAN D, GROWDONJ, CUPPLESL4, NEE b MYERSRH, ET AL: Absence of Duplication of Chromosome 21 Genes in Familial and Sporadic Alzheimer’s Disease. Science 1987, 23&M. 27.

TANZIRE, Bw, ED, IA’IT S& NEVE RL: The Amyloid Beta Protein Gene is not Duplicated in Brains from Patients with Alzheimeis Disease. Science 1987, 238:66&669.

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GOATE AM, CHARTIER-HARUN MC, MUUAN MC, BROWN J, CRAWFORD F, FIDANIL, GUIFFRAA, HAYNESA, IRVINGN, JAMESL, ET AL: Segregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer’s Disease. Nature . 1991, 349:704-706. Reports a single base substitution in exon 17 of the APP gene that occurs only in affected individuals in two FAD pedigrees. The substitution creates an amino acid change at position 717 of APP770 replacing a Val with an Ile. This is the first gene mutation associated with FAD. 29. ..

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E, CARMANMD, FER~UNDEZ-MADRID IJ, POWER MD, LIEBERBURG I, SJOERDG, VANDUWEN SG, BOTS G, LUYENDIJK W, FRANGIONE B: Mutation of the Alzheimer’s Disease Amy-

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CONNEALLY PM, TANZIRE, HAINES JL, WEXLERNS, PENCHAZADEH GK, HARPERPS, Fors’r~nu SE, CASSIMAN JJ, MYERSRH, YOUNG AB, ET AL: Huntington’s Disease: No Evidence for Locus Heterogeneity. Genomic- 1989, 5:304-308.

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BUCANM, ZIMMERM, WHALEYWL, POUSTKAA, YOUNGMANS, Ausrro BA, ORMONDROYD E, Sm B, POHLTM, MACDONALD M, ET AL.: Physical Maps of 4~16.3, the Area Expected to Contain the Huntington’s Disease Mutation. Genomics 1990, 6:1-15.

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JL, ZLMMER M, CHENGSV, YOUNGMAN S,WHA~FV~BUCANM,~OB~S~B,LEA~J,ET AL: Recombination Events Suggest Possible Locations for the Huntington’s Disease Gene. Neuron 1989, 3:183_190.

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WHALEYWI, MICHIEISF, MACDONALDME, ROMANOD, -R M, SMITHB, LEAVrrr J, BUCAN M, HAEVES JL, GILUAMTC, ET AL: Mapping of D4S98/S114/S113 Conlines the Huntington’s Defect to a Reduced Physical Region at the Telomere of Chromosome 4. Nuck+c Acid Res 1988, 16:1176+11780.

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Evidence from Family Studies that the Gene Causing Huntington’s Disease is Telomeric to D4S95 and D4S90. Am J Hum Genet 1989, 44~422425. 48. .

BATES GP, MACDONALDME, BAXENDAIE S, SEDIACEK 2, YOUNGMANS, ROMANOD, WHALF~WL, .&n-r0 BA, POUSTKA A, GUSEUAJF, ET AL: A YAC Telomere Clone Spanning a

Possible Location of the Huntington’s Disease Gene. Am J Hum &net 1990, 46~762-775. Multiple recombination events have suggested that the HD gene is contained in the most terminal region of 4p. In this paper, Bates et al. report a large yeast art&al chromosome clone containing the implicated region. 49. .

PRITCHARDC, CA~HERD, BULLL, Cox DR_ MYERSRM: A Cloned DNA segment from the Telomeric Region of Human Cbro-

disorders Tanzi

mosome 4p is not Detectably Rearranged in Huntington’s Disease Patients. Proc Nat1 Ad Sci USA 1990, 87:7%7313. Chromosome 4p telomeres are shown to lx structurally normal in HD patients as compared to control individuals. There were no obvious rearrangements in a suspected region for the HD gene defect. of Amyotrophic Lateral Sclerosis. In Human Motor Neuron Dtkease~ edited by Rowland IF’ [book]. New York: Raven Press 1982, pp 61-74.

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SIDDIQUET AND COUABORATORS: Linkage of a Gene Causing

Familial Amyotrophic Lateral Sclerosis to Chromosome 21 and Evidence of Genetic-Locus Heterogeneity. N Eng J med 1991, 324:1381-1384. Genetic linkage of inherited AIS to chromosome 21. The linkage peak occurs near the marker D21S58 that genetically maps 9 cM below the APP locus. Inherited AIS is also known to be genetic+ heterogeneous. It is estimated that just over 50% of inherited AIS involves a defect on _-i..‘ chromosome 21. T’,., i ..

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TANZI RE, HAINESJL WATKINSPC,,&&&

GD, WAIUCE MR, HALIEWELL R, WONG C, WEXLERN!%,‘CONNEALLY PM, GUSEUAJF: Genetic Linkage 3:12!&136.

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Map of Chromosome

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M, MULTHAUP G, FISCHER P, GARRUTO RM, BF(RELJTHER K, MASTERS CL, SIMMSS, GIBBSCJ. GAJDUSEK DC: Amyloid of Neurofibr&uy Tangles of Guamanian

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Parkinsonism-Dementia and Akxheimer Disease Share Identical Amino Acid Sequence. Proc Natl Acad Sci USA 1987, a4:20752077.

RE Tan& Molecular Neurogenetics Iaboratoly, Massachusetts Hospital, Charlestown, Massachusetts 02129, USA

General

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