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Confirmation of Genetic Heterogeneity in Limb-Girdle Muscular Dystrophy: Linkage of an Autosomal Dominant Form to Chromosome Sq Marcy C

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Confirmation of Genetic Heterogeneity in Limb-Girdle Muscular Dystrophy: Linkage of an Autosomal Dominant Form to Chromosome Sq Marcy C Am. J. Hum. Genet. 50:1211-1217, 1992 Confirmation of Genetic Heterogeneity in Limb-Girdle Muscular Dystrophy: Linkage of an Autosomal Dominant Form to Chromosome Sq Marcy C. Speer,*,t,1 Larry H. Yamaoka,* James H. Gilchrist,§ C. P. Gaskell,* Jeffrey M. Stajich,* Jeffery M. Vance,* Alexey Kazantsev,* Anselmo A. Lastra, Carol S. Haynes, * Jacques S. Beckmann, # Daniel Cohen, # James L. Weber, * * Allen D. Roses,* T and Margaret A. Pericak-Vance* *Division of Neurology, fUniversity Program in Genetics, and tDepartment of Zoology, Duke University, Durham, NC; §Department of Neurology, Rhode Island Hospital and Brown University, Providence; IlDepartment of Computer Science, University of North Carolina, Chapel Hill; #Centre d'Etude du Polymorphisme Humain, Paris; and **Marshfield Medical Research Foundation, Marshfield, WI Summary Limb-girdle muscular dystrophy (LGMD) is a clinically and genetically heterogeneous group of disorders, with both recessive and dominant forms reported. Recently, a series of recessive LGMD families were linked to chromosome 1 5q. We report herein the results of our linkage studies in a previously reported large autosomal dominant family. The LGMD gene in this family was localized to chromosome 5q22.3-31.3 by using a series of CA(n) microsatellite repeat markers. Linkage to 15q was excluded. These findings confirm genetic heterogeneity in this clinically diverse syndrome. Introduction Initial reports of LGMD described families with re- Limb-girdle muscular dystrophy (LGMD) is a progres- cessive inheritance (LGM2; MIM 253600) (Jackson sive muscular dystrophy with weakness beginning in and Strehler 1968; Shokeir and Kobrinsky 1976) and the hip and shoulder girdle and later progressing to the sporadic cases (Morton and Chung 1959). Later re- distal muscles. The LGMD diagnostic classification ports described families with dominant forms (LGM1; is ill-defined and heterogeneous (Morton and Chung MIM 159000) (Chutkow et al. 1986; Gilchrist et al. 1959; Brooke 1986). The diagnosis is clouded by tre- 1988). Thus, there is clearly heterogeneity in the mode mendous variability in expression, as well as by of genetic transmission in LGMD. Clinical heteroge- asymptomatic obligate heterozygotes in autosomal neity is also present, as evidenced both by the variation dominant families (DeCoster et al. 1974). The diagno- in age at onset and rate of progression and, to a lesser sis is further complicated in that other neurogenic/ extent, by the distribution of muscle weakness. Clini- myopathic disorders, particularly Becker muscular cal heterogeneity is present both within the dominant dystrophy (BMD) and Kugelberg-Welander syndrome class and between the dominant and recessive classes. (Kazakov et al. 1977; Coers et al. 1979), may clini- Recently, Beckmann et al. (1991) reported linkage cally mimic LGMD. Fascioscapulohumeral muscular of a series ofrecessive (LGM2) families, collected from dystrophy (FSHMD) should also be included in the the Isle of La Reunion, to the anonymous marker differential diagnosis of LGMD (Chyatte et al. 1966). D1SS2S (pTHH114), with a maximum LOD score (Z) of 5.52 at recombination fraction (0) = 0. Studies ReceivedJuly 30, 1991; final revision received January 24, 1992. by Young et al. (1991) have subsequently supported Address for correspondence and reprints: Margaret A. Pericak- this localization in a large, highly inbred Amish family Vance, Ph.D., Division of Neurology, Box 2900, Duke University (Jackson and Strehler 1968). Linkage studies reported Medical Center, Durham, NC 27710. © 1992 by The American Society of Human Genetics. All rights reserved. by Gilchrist et al. (1988) and Speer et al. (1989) failed 0002-9297/92/5006-0008$02.00 to find linkage in this form of LGMD. We report, in 1211 1212 Speer et al. this family, evidence for linkage to chromosome 5q fied from those of Weber and May (1989). The stan- and exclusion of linkage to chromosome 15q. dard PCR contained 0.03 jg of genomic DNA and 0.06 Rg of each primer in a volume of 15 gl. Amplifi- cation (27 cycles) was carried out in microtiter plates Subjects and Methods (Stratagene SCS 96 thermal cycler) with denaturing for 940C (1 min), 550C (2 min), 72"C (1 min). The Family 39: Ascertainment and Diagnostic Criteria final extension was for 6 min at 720C. After amplifi- This large LGM1 family (fig. 1) was ascertained cation, the products were separated on 6.5% denatur- through the Duke University Medical Center Neuro- ing polyacrylamide gels (IBI STS-45). Markers used muscular Research and Muscular Dystrophy Associa- for linkage of LGM1 to chromosome 5 are listed in tion Clinic. A detailed clinical description ofthe family table 1. has been reported elsewhere (Gilchrist et al. 1988). The family has been substantially expanded since the Statistical Analysis original report. Blood from 218 individuals was ob- LGM1 was analyzed as an autosomal dominant tained for creatine kinase testing, DNA extraction, trait with age-dependent penetrance. The gene fre- and lymphoblastoid cell line establishment. quency for LGM1 was fixed at 1/10,000. Two-point The diagnostic criteria for LGM1 were proximal leg Z values were calculated with the computer program weakness with or without proximal arm weakness, LIPED (Ott 1974). Allele frequencies for the RFLP absent ankle deep-tendon reflexes, and elevated cre- markers used were those published elsewhere (Kidd et atine kinase values or creatine kinase MB fractions. al. (1989) but did not deviate from those in our sample Obligate heterozygotes were classified as affected, in population. Allele frequencies for the dinucleotide re- the linkage analysis. Individuals with normal exami- peat markers were generated from a series of at least nations and with creatine kinase levels within normal 110 unrelated individuals (table 1). To facilitate com- limits were assigned heterozygosity risks based on puter analysis, the genotype results for the dinucleo- their age at examination. The probability of carrying tide repeat markers D5S119, DSS210, D5S207, and the LGM1 gene was generated from a normal distribu- IL-9 were recycled as suggested by Ott (1978), to mini- tion by assuming that the mean age at onset in this mize the number ofalleles while preserving the linkage family was 27.1 years (a = 8.5 years). Family mem- information. Support intervals about the estimate of bers who had signs or symptoms suggestive of LGM1 0 were calculated using the "one LOD score down" but who did not meet the strictly defined diagnostic method (Conneally et al. 1985). The analyses were criteria were considered to be of unknown disease sta- repeated using a low-risk penetrance for all unaffected tus. All spouses were considered normal with respect family members (i.e., an affecteds-only analysis). For to clinical status. This study includes genotype results this analysis, genotype information was preserved on on 218 individuals, 49 of whom were affected, 103 of all unaffected family members while eliminating the whom had normal examination, 28 of whom were phenotypic information regarding disease status, in considered of unknown disease status for this evalua- order to evaluate the contribution of known affecteds. tion, and 38 of whom were unrelated spouses. A genetic map for the markers D5S119, D5S207, D5S210, IL-9, and D5S70 was not available. There- Genotype Analysis fore, we attempted to generate a map based on the DNA was isolated from leukocytes or from trans- available information within the family. Map genera- formed cell lines. After digestion with restriction en- tion via a full likelihood analysis on the intact pedigree zymes, the DNA was transferred to Gene Screen Plus by the ILINK subprogram ofthe LINKAGE computer (NEN) and hybridized in 50O formamide according package on a 4/370 Sun workstation was not feasible, to methods described elsewhere (Yamaoka et al. for computational reasons. Reducing the family to its 1990). Polymorphic DNA markers were obtained nuclear components to facilitate mapping efforts led from the American Type Culture Collection or from to the loss of a considerable amount of information the investigators who developed them. Paternity and (e.g., for D5S210-D5S70 and D5S70-LGMD, the sample integrity were confirmed with the anonymous peak Z values were reduced by 25% and 71 %, respec- probe D2S44 (pYNH24) (Nakamura et al. 1987). tively). Thus, multiple pairwise mapping techniques Dinucleotide (CA) repeat polymorphism studies (Morton and Collins 1989) were used to generate a were carried out according to methods slightly modi- genetic map of this region. U *- W*°c CM. Caj Cu Va <_ ~~~~~~~~3° S~~~~C* -E ~d~~~~ -- -0 = -C. *S * S t)~~~.>2 02 C~~~~~ -o >y-E.n g± * A. < D-o-E C-s ~~ ;7 S 1 - IL 3; I0 3 =; ff)~~Ct 1214 Speer et al. Table I Markers with Allele Frequencies (for Microsatellite Repeat Markers) Used for Linkage of LGMD to Chromosome S Locus Marker Chromosomal Localization Fragment Sizea (% observed) Reference DSS119 ........ Mfd6 5q31.1-31.1 202 bp(2) 200 bp(6) 198 bp (2) Weber et al., submitted 194bp(4) 192 bp (63) 190 bp (23) J D5S207 ........ Mfd43 5q31.1-31.3 141 bp(32) 139 bp (52) Weber et al., submitted 137 bp(8) 135 bp(8)J DSS210 ........ Mfdl22 5q31.1-31.3 230bp(5) 228 bp(3) 222 bp (30) L Weber et al., submitted 220 bp(20)F 218 bp(8) 216 bp (32)J IL-9 5q22.3-31.3 139 bp (4) 137 bp(9) 133 bp (26) Polymeropoulos et al. 1991 131 bp (21) 129bp(9) J DSS70........ pTP5E 5q33-q35 As published Farber et al. 1988 a Included in the analysis are only those that appeared within the pedigree. Other fragment sizes were observed on the screening of random individuals but are not included in this table. Results chromosome 5q. The resulting two-point Z values are LGM1 was excluded for 45 cM proximal to shown in table 2. These markers all demonstrate link- D15S25 and for 40 cM distal to D15S25, the marker age to the LGM1 locus in this family.
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