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Human Molecular Genetics Pages 1377-1382
Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31
Introduction
Results
Discussion
Materials And Methods
   Linkage analysis
Acknowledgements
Abbreviations
References

Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31

Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31 Kazuo Isozumi1, Robert DeLong2, Jocelyn Kaplan1, Han-Xiang Deng1, Zafar Iqbal1, Wu-Yen Hung1, Kirk C. Wilhelmsen3, Afif Hentati1, Margaret A. Pericak-Vance4 and Teepu Siddique1,5,6,*

1Department of Neurology, 5Department of Cell and Molecular Biology, Northwestern University Medical School, 6Northwestern University Institute of Neuroscience, Chicago, IL 60611, USA, 2Division of Pediatric Neurology, 4Division of Neurology, Duke University Medical Center, Durham, NC 27710, USA and 3Department of Neurology, University of California San Francisco, San Francisco, CA 94110, USA

Received May 16, 1996; Revised and Accepted June 20, 1996

Scapuloperoneal (SP) syndromes are heterogeneous neuromuscular disorders which are characterized by weakness in the distribution of shoulder girdle and peroneal muscles. SP syndromes can resemble facioscapulohumeral muscular dystrophy (FSH) due to scapular weakness or Charcot-Marie-Tooth disease (CMT) due to atrophy of peroneal muscles. Both neurogenic and myopathic SP syndromes have been described. Locus for the myopathic form of SP syndrome (scapuloperoneal muscular dystrophy, SPMD) has recently been assigned to chromosome 12q. We previously described a large New England kindred exhibiting an autosomal dominant neurogenic SP syndrome (scapuloperoneal spinal muscular atrophy, SPSMA). Disease expression was more severe and progressive in successive generations, which suggested genetic anticipation. We performed genetic linkage analysis of this family with microsatellite markers and excluded the loci for FSH, CMT, SPMD and SMA (spinal muscular atrophy) in our family. Linkage in our SPSMA family (lod score >3) was established to seven microsatellite markers that map to chromosome 12q24.1-q24.31. The highest lod score with two-point linkage analysis was 6.67 ([theta] = 0.00) with marker D12S353. Multipoint analysis gave maximum lod scores of 7.38 between D12S354 and D12S79, and also 7.38 between D12S369 and NOS1 (neuronal nitric oxide synthase). The gene for SPSMA lies within the 19 cM interval between D12S338 and D12S366. This report establishes a locus for the neurogenic form of SP syndrome ~20 cM telomeric to the one described for the myopathic form of SP syndrome.

INTRODUCTION

Scapuloperoneal (SP) syndromes are heterogeneous neuromuscular disorders which are characterized by weakness in the distribution of shoulder girdle and peroneal muscles. Both neurogenic (scapuloperoneal spinal muscular atrophy, SPSMA) and myopathic (scapuloperoneal muscular dystrophy, SPMD) scapuloperoneal syndromes have been described (1 ,2 ). Locus for SPMD has recently been assigned to chromosome 12q (3 ).


Figure 1.Abridged pedigree of the SPSMA family used in the study illustrating the segregation of ten chromosome 12 loci. These are, from top to bottom, D12S330, D12S353, D12S105, D12S2072, D12S354, D12S1023, D12S369, D12S79, D12S2070 and NOS1. Squares and circles indicate males and females respectively. Solid symbols indicate affected, open symbols indicate non-affected, striped symbols indicate `probably affected' and the half-toned symbol indicates `clinical status unknown' members of the family. Slashed symbols show deceased individuals.

We previously described a large New England kindred of French-Canadian origin bearing the trait of an autosomal dominant neurogenic SP syndrome with variable expression that was transmitted through five generations (4 ) (MIM 181405). Features included congenital absence of muscles, progressive SP atrophy, laryngeal palsy, and progressive distal weakness and atrophy. The pattern of expression and progression varied in different branches of the family. Males were more severely affected than females, and disease expression was more severe and progressive in succeeding generations, suggesting genetic anticipation. The syndrome in our SPSMA family resembles the syndrome of Stark-Kaeser chronic scapuloperoneal amyotrophy (5 ,6 ) (MIM 181400), but we considered it a distinct entity.

Facial weakness is not present in SP syndromes and they are therefore different from the 4q35-linked facioscapulohumeral muscular dystrophy (FSH) (7 ). They sometimes resemble Charcot-Marie-Tooth diseases [CMTs: 17p11.2-linked CMT1A (8 ), 1q22-linked CMT1B (9 ), 1p36-p35-linked CMT2A (10 ) and 3q13-q22-linked CMT2B (11 )] because of peroneal muscular atrophy.

We performed genetic linkage analysis of microsatellite markers in our family with SPSMA and excluded the loci of FSH, CMTs, SPMD and SMA (spinal muscular atrophy). We then mapped the disease to a 19 cM interval on chromosome 12 ~20 cM telomeric to the locus described for SPMD. This interval includes the NOS1 (neuronal nitric oxide synthase) gene.

RESULTS

Thirty-six family members were enrolled into a genetic linkage study as indicated in the previous report (4 ). This included 19 affected and 12 unaffected subjects as well as five spouses, as shown in Figure 1 .

We first performed genetic linkage analysis with dinucleotide-repeat microsatellite markers (12 ) on the family with SPSMA and excluded the loci of FSH, CMTs, SPMD and SMA as the genetic locus for the disease in our family. Next, CHLC (Cooperative Human Linkage Center) screening set with tetranucleotide-repeat markers (13 ) was used to find the disease locus of SPSMA. The marker D12S2070 (CHLC.ATA25F09.40548) gave a significant two point lod score of 5.71 (3.58 for affected only). Then, dinucleotide-repeat markers flanking D12S2070 were analyzed in detail. The two point maximum likelihood data from chromosome 12 and other pertinent chromosomes are summarized in Table 1 . The highest two point lod score was 6.67 (5.61 for affected only) and was obtained with D12S353 at [theta] = 0.00. Multipoint analysis gave a maximum lod score of 7.38 (5.49 for affected only) between markers D12S354 and D12S79.


Table 1 . Two-point lod scores for linkage between SPSMA and markers on chromosome 1, 3, 4, 5, 12 and 17
* indicates no cross-over interval in SPMD (3), and ** indicates no cross-over interval in SPSMA. Kosambi cM information derived from the maps (12,33,34).


Due to apparent anticipation in our family we have investigated the possibility of pathological expansion of trinucleotide repeat motifs contained within two candidate loci recently assigned to the interval: the neuronal nitric oxide synthase (NOS1) gene and the human achaete-scute homologue 1 (ASCL1) gene (14 ).

The polymorphic characteristics of the NOS1 (AAT)n repeat motif within an intronic region of the gene were investigated as described previously (14 ), and four alleles were observed. NOS1 was found to be tightly linked to SPSMA. The two point lod scores between NOS1 and the SPSMA locus were Zmax = 3.94; [theta]max = 0.00. No recombination event was detected in affected members of the kindred. Multipoint analysis including NOS1 gave a maximum lod score of 7.38 (5.60 for affected only) between markers D12S369 and NOS1. However, no evidence for expansion of the (AAT)n was detected in affected individuals.

The ASCL1 gene contains a polymorphic (CAG)n repeat motif located in the proximal coding region (15 ). Analysis of the repeat motif in our family using the published primers (14 ) resulted in the detection of three alleles. Two point lod scores between ASCL1 and the SPSMA locus were Zmax = 4.89; [theta]max = 0.05. One recombination event was detected in the affected individual 35 of the kindred (Fig. 1 ), which confirmed the exclusion of this candidate gene in the SPSMA interval. No evidence for expansion of the (CAG)n repeat was detected in affected individuals.

Haplotype analysis gave critical crossovers as shown in Figure 1 . The upper limit of the interval is defined by a crossover in individual 35 with markers D12S338 (121 cM) and D12S330. The lower limit is defined by a crossover in individual 27 with markers NOS1 and D12S366 (140 cM). Since ASCL1 and NOS1 were mapped to chromosome 12q24.1 (14 ) and 12q24.2-q24.31 (16 ), respectively, SPSMA has been approximately mapped to the 19 cM interval on chromosome 12q24.1-q24.31, which is about 20 cM telomeric to the locus for SPMD (Table 1 , Fig. 2 ).


Figure 2.Schematic diagram of chromosome 12 indicating approximate location of the SPSMA locus in reference to other Mendelian neurological diseases and selected genes with data combined from the maps and references (3,12,14,17,33-36).

DISCUSSION

This study maps the gene responsible for SPSMA to a 19 cM interval on chromosome 12q24.1-q24.31. This lies in almost the same bands formerly reported to be linked to SCA2 (spinocerebellar ataxia 2) (14 ,17 ) (Fig. 2 ). Although both SPSMA and SCA2 are neurological disorders, the former affects peripheral nervous system and the latter primarily involves the central nervous system. Therefore, definite differences between the phenotypic expression of these two disorders exist, and they are obviously distinct diseases.

The locus for SPSMA is probably different from that of SPMD even though both loci are on chromosome 12q. They are from 7 (minimum) to 38 (maximum) cM distant (Table 1 , Fig. 2 ). In addition, histo-pathological findings are definitely different; the former is neurogenic (4 ) and the latter is myopathic (3 ). Linkage analysis excludes the locus for SPMD from that of SPSMA (Table 1 , Fig. 3 ). Therefore, we consider SPSMA and SPMD to be both clinically and genetically distinct entities. Also, loci of typical form of SMAs (spinal muscular atrophies, SMA1, SMA2 and SMA3) localized to 5q12.2-q13.3 (18 ) were also excluded (Table 1 ). Therefore, they are also both clinically and genetically different from SPSMA.


Figure 3.Multipoint lod scores of SPSMA vs. the markers D12S88 and D12S306 that flank the SPMD region.

In ourSPSMA kindred there is earlier onset, increasing severity and progressivity in successive generations, which suggests genetic anticipation. Genetic anticipation has also been described in other neurological disorders such as myotonic dystrophy (19 ), Kennedy disease (X-linked recessive spinobulbar muscular atrophy) (20 ), fragile X syndrome (21 ), spinocerebellar ataxia 1 (SCA1) (22 ), dentatorubral-pallidoluysian atrophy (DRPLA) (23 ), Huntington disease (24 ) and Machado-Joseph disease (SCA3) (25 ), all of which possess expansion of trinucleotide repeats, which are (CTG)n, (CAG)n, (CGG)n, (CAG)n, (CAG)n, (CAG)n and (CAG)n, respectively (26 ). Genetic anticipation was also described in SCA2 (27 ), although no expanded triplet repeat has been demonstrated at present.

Neuronal NOS is responsible for the production of nitric oxide (NO), a neurotransmitter, which also plays a role in nervous system morphogenesis and synaptic plasticity (28 ). Excessive production of highly reactive NO may be responsible for the neurotoxicity that contributes to the symptomatology of strokes and neurodegenerative diseases (28 ). NOS1 gene consists of 29 exons with 28 intronic regions (29 ). There are no triplet repeat motifs in coding regions of NOS1 gene (29 ). One known triplet repeat motif in intronic regions of the gene is (AAT)n (14 ), and it was not found to be expanded in SPSMA. However, expansion of other triplet repeat motifs which have not been screened might be possible, and should be investigated.

Other candidate genes whose loci are mapped with overlap to chromosome 12q24.1-q24.31 include ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, [beta]-polypeptide), ATP2A2/ATP2B (ATPase, Ca++ dependent, slow-twitch, cardiac muscle-2) and MYL2 (myosin, light polypeptide-2, regulatory, cardiac, slow). Also, candidate genes with loci on chromosome 12 which are not localized at present include MYBPC1 (myosin-binding protein C, slow type), MYF5 (myogenic factor-5), MYF6 (myogenic factor-6), NTS (neurotensin) and TUBAL1 (tubulin, [alpha]-like-1) (OMIM: Online Mendelian Inheritance in Man, GDB: Genome Data Base).

Our study has genetically separated the neurogenic form from the myopathic one of SP syndromes, and also shown that SP syndromes are genetically different from FSH and CMTs.

MATERIALS AND METHODS

Blood samples were obtained from 19 affected members, 12 non-affected members and five spouses for linkage analysis. Genomic DNA was extracted from these samples using salting out method (30 ). PCR amplification (31 ) from 30 ng DNA samples was performed utilizing [[alpha]-32P]dGTP. PCR conditions were: 95oC for 5 min, followed by 32 cycles of 95oC for 1 min, 55oC (51oC for NOS1) for 30 s, 72oC for 1 min, then 72oC extension for 10 min. The products were separated by denaturing polyacrylamide gel electrophoresis and visualized by autoradiography.

Linkage analysis

Two-point and multipoint linkage analysis were performed using the MLINK and the LINKMAP programs of the LINKAGE 5.1 package (32 ), assuming a gene frequency for the disease locus of 0.0001 and penetrance of 0.90. Calculations with markers used the current allele frequencies determined from analysis of eight CEPH families.

ACKNOWLEDGMENTS

We would like to thank Dr Rebecca Twells for his scientific advice on NOS1/ASCL1 PCR assay, and Dr Gang Deng, Tony Juneja, Janice Caliendo, Wenjie Chen and Daniel Heintz for their technical assistance. This work was supported by National Institutes of Health (TS), Les Turner ALS Foundation (TS), the Muscular Dystrophy Association of America (TS, ZI, MP-V), NINDS26630 (MP-V) and Keio-Northwestern Academic Exchange Program (KI).

ABBREVIATIONS

ASCL, achaete-scute homologue; CMT, Charcot-Marie-Tooth disease; DRPLA, dentatorubral-pallidoluysian atrophy; FSH, facioscapulohumeral muscular dystrophy; NO, nitric oxide; NOS, nitric oxide synthase; SCA, spinocerebellar ataxia; SMA, spinal muscular atrophy; SP, scapuloperoneal; SPMD, scapuloperoneal muscular dystrophy; SPSMA, scapuloperoneal spinal muscular atrophy.

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*To whom correspondence should be addressed

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