HUMAN MUTATION 1:79 (1992)
LETTER TO THE EDZTOR
Fibrillin (IBNl) Mutations in Marfan syndrome Communicated by Richard G.H. Cotton
To the Editor: Marfan syndrome (MFS), a disorder of connective tissue inherited as an autosomal dominant, has been mapped to 15q21.1. (Kainulainen et al., 1990, 1991; Tsipouras et al., 1991; Dietz et al., 1991a) in the same region as the fibrillin gene, FBNl (Lee et al., 1991; Maslen et al., 1991: Magenis et al., 1991; Dietz et al., 1991b). Evidence that mutations in FBNl cause MFS comes from the finding of a missense G-C alteration at nucleotide 716, substituting proline for arginine (R239P), in two sporadic cases (Dietz et al., 1991b), and a ?-A alteration in nucleotide 1409, substituting serine for cystine (C1409S), in three generations of a MFS family (Dietz et al., 1992). We have searched for those two mutations in samples from 46 unrelated affected individuals, each representing a family in which MFS was segregating, as well as from 8 sporadic cases. Polymerase chain reaction amplification was carried out using primers MUT-IS and F-2AS and R239P (Dietz et al., 1991b), and primers F13S and Fl2AS for C1409S (Dietz et al., 1992). Product, including positive and negative amplified control material, was dot-blotted onto nylon membranes and probed with allele-specific oligonucleotides (Dietz et al., 1991b, 1992). No new examples of either R239P or C1409S were found. Combining our data with that of Dietz et al. (1991b, 1992) shows that R232P has now been found twice in 111 cases and C1409S once in 140 cases (mutations being scored once for each sporadic case and once for each family segregating the gene). It must be concluded that many different FBNl mutations are likely to be responsible for MFS, and that the search for these is only the beginning. REFERENCES Dietz, HC, Pyeritz, RE, Hall BD, Cadle, RG, Hamosh A, Schwartz J , Meyers DA, Francomano C A (1991a) The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15q21.3. Genomics 9:355-361.
0 1992 WILEY-LISS. INC.
Dietz, HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, Stetten G, Meyers DA, Francomano C A (1991b). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature (London) 352:337-339. Dietz HC, Pyeritz RE, Puffenberger EG, Kendzior RJ, Corson JM, Maslen CL, Sakai LY, Francomano CA, Cutting GR (1992) Marfan phenotype variability in a family segregating a missense mutation on the EGF,like motif of the fibrillin gene. 1 Clin Invest, in press. Kainulainen K, Pulkkiueu L, Savolainen A, Kattila 1, Peltonene L (1990) Location on chromosome 15 of the gene defect causing Marfan syndrome. New Engl J Med 323:935-939. Kainulainen K, Steinmann B, Collins F, Dietz HC, Francomano C A , Child A , Kilpatrick MW, Brock DJH, Keston M, Pyeritz RE, Peltonen L (1991) Marfan syndrome: no evidence for heterogeneity in different populations, and more precise mapping of the gene. Am J Hum Genet 49:662-667. Lee B, Gcdhey M, Vitale E, Hori H , Mattei MG, Sarfarazi M, Tsipouras P, Ramirez F, Hollister DW (1991) Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature (London) 352330-334. Magenis RE, Maslen CL, Smith L, Allen L, Sakai LY (1991) Localisation of the fibrillin (FBN) gene to chromosome 15, band q21.1. Genomics 11:346-351. Maslen CL, Corson GM, Maddox BK, Glanville E, Sakai LY (1991) Partial sequence of a condidate gene for Marfan syndrome. Nature (London) 352:334-337. Tsipouras P, Sarfarazi M, Devi A, Weiffenbach B, Boxer M (1991) Marfan syndrome is closely linked to a marker on chromosome 15q1.5-q2.1. Proc Natl Acad Sci USA 88:4486-4488.
Caroline Hayward Marion Keston David J.H. Brock* Human Genetics Unit The University of Edinburgh Western General Hospital Edinburgh, UK Harry C. Dietz Center for Medical Genetics The Johns Hopkins School of Medicine Baltimore, Maryland
Received February 4, 1992; accepted February 27,1992 *To whom reprint requestdcorrespondence should be addressed.
LETTER TO THE EDZTOR
Fibrillin (IBNl) Mutations in Marfan syndrome Communicated by Richard G.H. Cotton
To the Editor: Marfan syndrome (MFS), a disorder of connective tissue inherited as an autosomal dominant, has been mapped to 15q21.1. (Kainulainen et al., 1990, 1991; Tsipouras et al., 1991; Dietz et al., 1991a) in the same region as the fibrillin gene, FBNl (Lee et al., 1991; Maslen et al., 1991: Magenis et al., 1991; Dietz et al., 1991b). Evidence that mutations in FBNl cause MFS comes from the finding of a missense G-C alteration at nucleotide 716, substituting proline for arginine (R239P), in two sporadic cases (Dietz et al., 1991b), and a ?-A alteration in nucleotide 1409, substituting serine for cystine (C1409S), in three generations of a MFS family (Dietz et al., 1992). We have searched for those two mutations in samples from 46 unrelated affected individuals, each representing a family in which MFS was segregating, as well as from 8 sporadic cases. Polymerase chain reaction amplification was carried out using primers MUT-IS and F-2AS and R239P (Dietz et al., 1991b), and primers F13S and Fl2AS for C1409S (Dietz et al., 1992). Product, including positive and negative amplified control material, was dot-blotted onto nylon membranes and probed with allele-specific oligonucleotides (Dietz et al., 1991b, 1992). No new examples of either R239P or C1409S were found. Combining our data with that of Dietz et al. (1991b, 1992) shows that R232P has now been found twice in 111 cases and C1409S once in 140 cases (mutations being scored once for each sporadic case and once for each family segregating the gene). It must be concluded that many different FBNl mutations are likely to be responsible for MFS, and that the search for these is only the beginning. REFERENCES Dietz, HC, Pyeritz, RE, Hall BD, Cadle, RG, Hamosh A, Schwartz J , Meyers DA, Francomano C A (1991a) The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15q21.3. Genomics 9:355-361.
0 1992 WILEY-LISS. INC.
Dietz, HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, Stetten G, Meyers DA, Francomano C A (1991b). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature (London) 352:337-339. Dietz HC, Pyeritz RE, Puffenberger EG, Kendzior RJ, Corson JM, Maslen CL, Sakai LY, Francomano CA, Cutting GR (1992) Marfan phenotype variability in a family segregating a missense mutation on the EGF,like motif of the fibrillin gene. 1 Clin Invest, in press. Kainulainen K, Pulkkiueu L, Savolainen A, Kattila 1, Peltonene L (1990) Location on chromosome 15 of the gene defect causing Marfan syndrome. New Engl J Med 323:935-939. Kainulainen K, Steinmann B, Collins F, Dietz HC, Francomano C A , Child A , Kilpatrick MW, Brock DJH, Keston M, Pyeritz RE, Peltonen L (1991) Marfan syndrome: no evidence for heterogeneity in different populations, and more precise mapping of the gene. Am J Hum Genet 49:662-667. Lee B, Gcdhey M, Vitale E, Hori H , Mattei MG, Sarfarazi M, Tsipouras P, Ramirez F, Hollister DW (1991) Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature (London) 352330-334. Magenis RE, Maslen CL, Smith L, Allen L, Sakai LY (1991) Localisation of the fibrillin (FBN) gene to chromosome 15, band q21.1. Genomics 11:346-351. Maslen CL, Corson GM, Maddox BK, Glanville E, Sakai LY (1991) Partial sequence of a condidate gene for Marfan syndrome. Nature (London) 352:334-337. Tsipouras P, Sarfarazi M, Devi A, Weiffenbach B, Boxer M (1991) Marfan syndrome is closely linked to a marker on chromosome 15q1.5-q2.1. Proc Natl Acad Sci USA 88:4486-4488.
Caroline Hayward Marion Keston David J.H. Brock* Human Genetics Unit The University of Edinburgh Western General Hospital Edinburgh, UK Harry C. Dietz Center for Medical Genetics The Johns Hopkins School of Medicine Baltimore, Maryland
Received February 4, 1992; accepted February 27,1992 *To whom reprint requestdcorrespondence should be addressed.
