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A New Form of Autosomal Dominant Limb-Girdle Muscular Dystrophy (LGMD1G) with Progressive Fingers and Toes Flexion Limitation Maps to Chromosome 4P21

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A New Form of Autosomal Dominant Limb-Girdle Muscular Dystrophy (LGMD1G) with Progressive Fingers and Toes Flexion Limitation Maps to Chromosome 4P21 European Journal of Human Genetics (2004) 12, 1033–1040 & 2004 Nature Publishing Group All rights reserved 1018-4813/04 $30.00 www.nature.com/ejhg ARTICLE A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21 Alessandra Starling1, Fernando Kok2, Maria Rita Passos-Bueno1, Mariz Vainzof1 and Mayana Zatz*,1 1Human Genome Research Center, Department of Biology, University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 2Department of Neurology, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil Limb-girdle muscular dystrophy (LGMD) is a genetic disorder characterized by progressive weakness of pelvic and scapular girdles and great clinical variability. It is a highly heterogeneous disease with 16 identified loci: six of them autosomal dominant (AD) (LGMD1) and 10 autosomal recessive (AR) (LGMD2). The responsible genes are known for three of the AD-LGMD and for all 10 AR-LGMD. Linkage analysis excluded these 16 loci in a Brazilian-Caucasian family with 12 patients affected by AD late-onset LGMD associated with progressive fingers and toes flexion limitation. Biceps muscle biopsy from one of the patients showed a predominantly myopathic histopathological pattern, associated with rimmed vacuoles. A genomewide scan was performed which mapped a new locus for this disorder at 4p21 with a maximum two-point lod score of 6.62 for marker D4S2964. Flanking markers place this locus between D4S2947 and D4S2409, within an interval of 9 cM. We propose to classify this AD form of LGMD as LGMD1G. European Journal of Human Genetics (2004) 12, 1033–1040. doi:10.1038/sj.ejhg.5201289 Published online 15 September 2004 Keywords: LGMD1G; linkage analysis; new locus; muscular dystrophy; fingers flexion limitation Introduction comprise less than 10% of all cases.2–4 Speer et al5 mapped Limb-girdle muscular dystrophy (LGMD) is a heteroge- the first locus for LGMD1 to 5q (LGMD1A) and demon- neous genetic disorder characterized by progressive weak- strated evidence of genetic heterogeneity.6 LGMD1A is ness of pelvic and scapular girdles and great clinical caused by a defect in the myotilin gene.7 LGMD1B, located variability. At least 16 loci for LGMD have been mapped at 1q11,8 is caused by a defect in lamin A/C9 and LGMD1C, so far: six for autosomal dominant (AD) LGMD, known as located at 3p25, is caused by deficiency in caveolin-3.10,11 LGMD11 and 10 for autosomal recessive (AR) LGMD, also The locus for LGMD1D, LGMD1E and LGMD1F are classified as LGDM2.2 Responsible genes have already been respectively located at 7q,12 6q2313 and 7q32,14 but their identified for all 10 AR-LGMD forms but only for three AD genes were not yet identified. forms. The dominant forms are relatively rare and We have ascertained a Brazilian-Caucasian family with 12 individuals affected by a mild late-onset form of LGMD associated with progressive fingers and toes flexion limita- *Correspondence: Dr M Zatz, Departamento de Biologia, Instituto de tion. They are distributed in three generations with a clear Biocieˆncias, Rua do Mata˜o 277/212, Cidade Universita´ria, USP, Sa˜o Paulo, AD pattern of inheritance (Figure 1). Linkage analysis Brazil. Tel: þ 55 11 30917563; Fax: þ 55 11 30917419; E-mail: [email protected] allowed us to exclude all six known LGMD1 loci as Received 30 March 2004; revised 11 June 2004; accepted 25 June 2004 responsible for the disease. Therefore, we undertook a European Journal of Human Genetics 1034 Figure 1 Pedigree of the LGMD1G family with haplotypes from the 4p21 region. I 1 2 II 1 2 3 4 5 6 7 8 9 The seventh autosomal dominant LGMD 10 13 markers 10 13 10 13 8 8 10 13 2 13 D4S1592 11 14 16 14 16 14 16 14 13 16 16 14 2 1 D4S392 2 4 2 4 2 3 2 4 1 4 D4S2393 4 2 3 3 3 2 3 2 1 1 3 2 2 4 D4S2363 2 5 2 5 4 1 2 5 5 5 D4S2630 4 7 6 2 6 7 6 7 6 3 6 7 12 6 D4S2947 12 9 12 9 8 13 12 9 8 9 D4S2964 6 8 6 6 6 8 6 8 11 9 6 8 5 4 D4S1534 5 1 5 1 2 5 1 1 1 1 D4S2409 10 8 8 9 8 8 8 9 9 8 9 8 11 6 D4S414 11 8 11 6 11 11 6 8 11 8 A Starling 16 9 D4S1572 16 12 16 9 10 15 16 12 10 12 D4S406 III 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 et al 8 13 10 12 8 8 13 12 10 9 13 9 10 9 13 9 10 8 10 13 10 13 10 10 13 8 13 8 13 8 10 8 10 8 11 14 16 15 11 11 14 15 16 8 14 8 16 8 14 8 16 13 16 13 16 9 14 16 16 16 14 13 14 16 16 16 16 16 2 4 2 3 2 4 1 3 2 3 1 3 1 3 1 3 2 2 2 2 2 5 4 3 2 3 4 2 4 3 2 3 2 3 4 2 3 3 1 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 2 1 3 1 2 1 2 1 3 1 3 3 3 5 2 5 3 3 4 5 4 4 4 4 4 4 2 4 2 4 2 4 2 4 5 1 2 1 5 4 5 1 2 1 2 5 3 7 6 6 6 5 2 6 2 1 2 1 2 1 6 1 6 5 6 5 6 5 7 3 6 3 7 6 7 3 6 3 6 5 9 9 12 15 15 6 6 15 6 9 6 9 6 9 12 9 12 16 12 16 12 16 9 13 12 13 9 8 9 13 12 13 9 14 9 8 6 6 9 11 6 11 6 11 6 11 6 11 6 6 6 7 6 7 6 7 8 9 6 9 8 11 8 9 6 9 8 11 2 1 5 3 2 2 4 3 4 4 4 4 4 4 5 4 5 2 5 2 5 2 1 5 5 5 1 2 1 5 5 5 1 4 6 8 8 8 9 10 9 8 9 10 9 10 9 10 8 10 8 9 8 9 8 9 9 8 8 8 9 9 9 8 8 8 8 8 6 8 11 11 8 8 6 11 6 6 6 6 6 6 11 6 8 5 11 5 8 5 6 11 11 11 6 11 6 11 11 11 8 7 10 12 16 12 - - 9 12 9 10 9 10 9 10 16 12 12 13 16 13 12 13 9 15 16 10 9 10 9 10 16 15 12 15 IV 1 2 3 4 10 8 10 8 10 8 10 8 16 11 16 11 16 11 16 11 2 2 2 4 2 2 2 2 3 1 3 2 3 1 3 1 2 3 2 3 2 3 2 3 6 6 6 5 6 6 6 6 12 15 12 6 12 15 15 15 6 9 6 11 6 9 6 9 5 2 5 2 5 2 3 2 8 9 8 10 8 9 8 9 11 8 11 8 11 8 11 8 16 16 16 12 16 12 12 16 The seventh autosomal dominant LGMD A Starling et al 1035 genomewide scan using microsatellite markers. Here we Complementary examinations report the identification of a new LGMD1 locus at 4p21 Hands X-ray of patient IV-1 was normal. Electrocardiogram that we propose to call LGMD1G, further increasing and echocardiogram results were normal for four patients genetic heterogeneity for AD-LGMD. that were submitted to these examinations within the last 6 months (Figure 1, patients III-2, III-15, IV-2 and IV-3). A muscle biopsy was taken from biceps muscle from patient Subjects and methods IV-3, a 38-year-old male. It was cryoprotected and snap Subjects frozen in liquid nitrogen. Routine histological and histo- The index case (IV-1, Figure 1) was referred to the Human chemical analysis include staining for hematoxylin and Genome Research Center, at the Department of Biology, eosin (H&E), modified Gomori trichrome, SDH, NADH, University of Sa˜o Paulo for diagnosis and genetic studies. acid phosphatases, and ATPase at pH 9.4 and 4.315 The diagnosis of LGMD was based on clinical course, Proteins analysis were performed through immunofluor- neurological examination, electromyography and a muscle escence (IF) and Western blot (WB) methodologies, as biopsy, which showed a primary myopathic pattern. previously described.16,17 The following antibodies were Subsequent analysis of the family’s pedigree revealed the used: dystrophin,18 sarcoglycans a, b, g and d,19 calpain- existence of 12 affected patients (eight male and four 3,20, dysferlin21 and telethonin.22 female patients) distributed in three generations, display- ing AD inheritance (Figure 1). In total, 10 patients (seven male and three female patients) were clinically and neurologically examined by one of us (FK, Table 1). The Microsatellite marker analysis study was conducted after informed consent and was DNA was isolated from blood by standard methods.
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