Founder-haplotype analysis in Fukuyama-type congenital muscular dystrophy (FCMD)

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive, severe muscular dystrophy associated with brain anomalies. After our initial mapping of the FCMD locus to 9q31–33, we performed linkage disequilibrium analysis, which led us to suspect that the FCMD gene lay within a region of less than 100 kb containing D9S2107. In the present study, we developed two new microsatellites (D9S2170 and D9S2171) in close vicinity to D9S2107 and examined haplotypes of FCMD chromosomes by using four markers (cen-D9S2105-D9S2170-D9S2171-D9S2107-tel). As 82% of the FCMD chromosomes that we examined shared the founder haplotype (138–192–147–183) and 94% of the FCMD patients in our panel carried founder haplotypes on one or both chromosomes, the data supported the hypothesis of a single founder of this disease in the Japanese population. Eight haplotypes different from the founder’s were observed in FCMD chromosomes, indicating that eight different FCMD mutations in addition to the founder’s have occurred in Japan. Moreover, we have detected several historical recombinations that have disrupted the founder haplotype at D9S2105 or D9S2170 and conclude that the FCMD gene is probably located just centromeric to D9S2170. Received: 16 May 1998 / Accepted: 10 June 1998     

Molecular genetic evidence of clinical heterogeneity in Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive severe muscular dystrophy associated with brain malformation. The gene responsible for FCMD was mapped to chromosome 9q31, a region in which convincing evidence of strong linkage disequilibrium between FCMD and mfd220 (D9S306) was recently found. FCMD is also characterized clinically by a peak motor function which, at best, allows patients to sit unassisted or slide on the buttocks. However, a small fraction of patients acquire the capacity to walk unassisted. Whether such ambulant cases belong to the FCMD spectrum or to a different disease entity has been a topic of considerable debate. We performed linkage analysis for ten families with ambulant cases using DNA markers flanking the FCMD locus. The mfd220 locus yielded a significant lod score of 3.09 for ambulant FCMD. We also found evidence for linkage disequilibrium between ambulant FCMD and mfd220. We further conducted haplotype analysis in FCMD siblings with different phenotypes, one of whom was ambulant while the other was not. The results indicate that the FCMD siblings share exactly the same haplotype at nine marker loci spanning 23.3 cM surrounding the FCMD locus. On the basis of these results, we conclude that, genetically, ambulant cases are, in fact, part of the FCMD spectrum. Received: 28 June 1996     

Refined Mapping of a Gene Responsible for Fukuyama-Type Congenital Muscular Dystrophy: Evidence for Strong Linkage Disequilibrium

Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain. After our initial mapping of the FCMD locus to chromosome 9q31-33, we further defined the locus within a region of ~5 cM between loci D9S127 and CA246, by homozygosity mapping in patients born to consanguineous marriages and by recombination analyses in other families. We also found evidence for strong linkage disequilibrium between FCMD and a polymorphic microsatellite marker, mfd220, which showed no recombination and a lod score of (Z) 17.49. A “111-bp” allele for the mfd220 locus was observed in 22 (34%) of 64 FCMD chromosomes, but it was present in only 1 of 120 normal chromosomes. This allelic association with FCMD was highly significant (χ² =50.7; P<.0001). Hence, we suspect that the FCMD gene could lie within a few hundred kilobases of the mfd220 locus.     

Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping.

Muscle-eye-brain disease (MEB) is an autosomal recessive disease of unknown etiology characterized by severe mental retardation, ocular abnormalities, congenital muscular dystrophy, and a polymicrogyria-pachygyria-type neuronal migration disorder of the brain. A similar combination of muscle and brain involvement is also seen in Walker-Warburg syndrome (WWS) and Fukuyama congenital muscular dystrophy (FCMD). Whereas the gene underlying FCMD has been mapped and cloned, the genetic location of the WWS gene is still unknown. Here we report the assignment of the MEB gene to chromosome 1p32-p34 by linkage analysis and homozygosity mapping in eight families with 12 affected individuals. After a genomewide search for linkage in four affected sib pairs had pinpointed the assignment to 1p, the MEB locus was more precisely assigned to a 9-cM interval flanked by markers D1S200 proximally and D1S211 distally. Multipoint linkage analysis gave a maximum LOD score of 6.17 at locus D1S2677. These findings provide a starting point for the positional cloning of the disease gene, which may play an important role in muscle function and brain development. It also provides an opportunity to test other congenital muscular dystrophy phenotypes, in particular WWS, for linkage to the same locus.     

A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus.

Characterized by proximal muscle weakness and wasting, limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of clinical disorders. Previous reports have documented either autosomal dominant or autosomal recessive modes of inheritance, with genetic linkage studies providing evidence for the existence of at least 12 distinct loci. Gene products have been identified for five genes responsible for autosomal recessive forms of the disorder. We performed a genome scan using pooled DNA from a large Hutterite kindred in which the affected members display a mild form of autosomal recessive LGMD. A total of 200 markers were used to screen pools of DNA from patients and their siblings. Linkage between the LGMD locus and D9S302 (maximum LOD score 5.99 at recombination fraction .03) was established. Since this marker resides within the chromosomal region known to harbor the gene causing Fukuyama congenital muscular dystrophy (FCMD), we expanded our investigations, to include additional markers in chromosome region 9q31-q34.1. Haplotype analysis revealed five recombinations that place the LGMD locus distal to the FCMD locus. The LGMD locus maps close to D9S934 (maximum multipoint LOD score 7.61) in a region that is estimated to be approximately 4.4 Mb (Genetic Location Database composite map). On the basis of an inferred ancestral recombination, the gene may lie in a 300-kb region between D9S302 and D9S934. Our results provide compelling evidence that yet another gene is involved in LGMD; we suggest that it be named "LGMD2H."     

Age and origin of the FCMD 3′-untranslated-region retrotransposal insertion mutation causing Fukuyama-type congenital muscular dystrophy in the Japanese population

Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive disorder with a high prevalence in the Japanese population, is characterised by severe muscular dystrophy associated with brain malformation (cortical dysgenesis) and mental retardation. In Japan, 87% of FCMD-bearing chromosomes carry a 3-kb retrotransposal insertion of tandemly repeated sequences within the disease gene recently identified on chromosome 9q31, and most of them share a common founder haplotype. FCMD is the first human disease known to be caused primarily by an ancient retrotransposal integration. By applying two methods for the study of linkage disequilibrium between flanking polymorphic markers and the disease locus, and of its decay over time, the age of the insertion mutation causing FCMD in Japanese patients is calculated to be approximately 102 generations (95% confidence interval: 86-117 g), or slightly less. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes back to the time (or a few centuries before) the Yayoi people started migrating to Japan from the Korean peninsula. This finding makes the molecular population genetics of FCMD understandable in the context of Japan's history and the founder effect consistent with the prevalent theory on the origins of the modern Japanese population.     

Evidence of a founder effect and refinement of the hereditary neuralgic amyotrophy (HNA) locus on 17q25 in American families

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder that is associated with episodic recurrent brachial plexus neuropathy. A mutation for HNA maps to chromosome 17q25. To refine the HNA locus further, we carried out genetic linkage studies in seven pedigrees with a high density set of DNA markers from chromosome 17q25. All pedigrees demonstrated linkage to chromosome 17q25, and an analysis of recombinant events placed the HNA locus within an interval of approximately 1 Mb flanked by markers D17S722 and D17S802. In order to test the power of linkage disequilibrium mapping, we compared genotypes of 12 markers from seven pedigrees that were from the United States and that showed linkage to chromosome 17q25. The haplotypes identified a founder effect in six of the seven pedigrees with a minimal shared haplotype that further refines the HNA locus to an interval of approximately 500 kb. These findings suggest that, for the pedigrees from the United States, there are at least two different mutations in the HNA gene.     

Isolation of additional polymorphic clones from the cystic fibrosis region, using chromosome jumping from D7S8.

The cystic fibrosis (CF) locus has been located, by both linkage analysis and physical mapping, to a 900-kb region of 7q22-31 flanked by D7S8 (J3.11) and D7S23 (XV-2c). Using a 100-kb general jumping library, we isolated two sequential jump clones, J31 and J29, to one side of the D7S8 region and one jump clone, J32, to the other side of D7S8, so that the total region covered is about 300 kb. Three new RFLPs were detected by J29 and J32. Using PFGE mapping and the three jump clones, we found it possible to orient D7S8 on the chromosome and, by linkage analysis, to further narrow the CF region by 100 kb. The orientation of D7S8 will be useful for directing the isolation of other jump clones toward the CF locus. Though the newly described RFLPs are in considerable linkage disequilibrium with D7S8 polymorphisms, they increase the informativeness of genetic markers in the D7S8 region and should be useful in prenatal diagnosis.     

Significant linkage disequilibrium between the Huntington disease gene and the loci D4S10 and D4S95 in the Dutch population.

Significant linkage disequilibrium has been found between the Huntington disease (HD) gene and DNA markers located around D4S95 and D4S98. The linkage-disequilibrium studies favor the proximal location of the HD gene, in contrast to the conflicting results of recombination analyses. We have analyzed 45 Dutch HD families with 19 DNA markers and have calculated the strength of linkage disequilibrium. Highly significant linkage disequilibrium has been detected with D4S95, consistent with the studies in other populations. In contrast with most other studies, however, the area of linkage disequilibrium extends from D4S10 proximally to D4S95, covering 1,100 kb. These results confirm that the HD gene most likely maps near D4S95.