H. El-shanti et al., Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q, AM J HU GEN, 66(4), 2000, pp. 1229-1236
Citations number
42
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics
Wolfram syndrome, which is sometimes referred to as "DIDMOAD" (diabetes ins
ipidus, diabetes mellitus, optic atrophy, and deafness), is an autosomal re
cessive neurodegenerative disorder for which only insulin-dependent diabete
s mellitus and optic atrophy are necessary to make the diagnosis. Researche
rs have mapped Wolfram syndrome to chromosome 4p16.1, and, recently, a gene
encoding a putative transmembrane protein has been cloned and mutations ha
ve been identified in patients. To pursue the possibility of locus heteroge
neity, 16 patients from four different families were recruited. These patie
nts, who have the Wolfram syndrome phenotype, also have additional features
that have not previously been reported. There is an absence of diabetes in
sipidus in all affected family members. In addition, several patients have
profound upper gastrointestinal ulceration and bleeding. With the use of th
ree microsatellite markers (D4S432, D4S3023, and D4S2366) reported to be li
nked to the chromosome 4p16.1 locus, we significantly excluded linkage in t
hree of the fear families. The two affected individuals in one family showe
d homozygosity for all three markers from the region of linkage on chromoso
me 4p16.1. For the other three families, genetic heterogeneity for Wolfram
syndrome was verified by demonstration of linkage to chromosome 4q22-24. In
conclusion, we report the unique clinical findings and linkage-analysis re
sults of 16 patients with Wolfram syndrome and provide further evidence for
the genetic heterogeneity of this disorder. We also provide data on a new
locus that plays a role in the etiology of insulin-dependent diabetes melli
tus.