Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24

Abstract

Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.

Hereditary motor and sensory neuropathy – Lom (HMSNL): refined genetic mapping in Romani (Gypsy) families from several European countries

“…The participating centres have reported consistent clinical ®ndings which allow the de®nition of the HMSNL phenotype [1,3,4,6,7]. Onset of symptoms is in the ®rst decade of life.…”

“…These included nine microsatellites¯anking the HMSNL region, namely 41F08, D8S557, D8S1835 and D8S558 on the centromeric side, and D8S256, D8S1708, D8S1746, D8S1796 and D8S1462 on the telomeric side. A total of 23 markers were located in the interval between D8S558 and D8S256, de®ned in the initial study as the HMSNL gene region [1], Three of these microsatellites, namely D8S529, D8S378 and AFM116yh8 have been published previously and are available through the public genome databases. The remaining 20 polymorphic microsatellites have been identi®ed as part of this study.…”

“…The initial gene mapping study [1] placed the HMSNL gene between markers D8S558 and D8S256. According to public databases, the interval contained ®ve known polymorphic microsatellites positioned in the order cen-D8S558-D8S529/D8S378-AFM116yh8-D8S256-tel.…”

“…Hereditary motor and sensory neuropathy type Lom (HMSNL) is a novel autosomal recessive demyelinating neuropathy associated with deafness, which was initially identi®ed in Roma (Gypsy) families from Bulgaria [1,2]. The HMSNL gene has been mapped to 8q24 [1].…”

“…The HMSNL gene has been mapped to 8q24 [1]. The conserved polymorphic haplotypes on 8q24, shared by all disease chromosomes in the original group of affected families, suggested genetic homogeneity and homozygosity for a single founder mutation.…”