Presence of a major WFS1 mutation in Spanish wolfram syndrome pedigrees

Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disease m ainly characterized by familial diabetes mellitus and optic atrophy. WS pat ients frequently present with other clinical features such as diabetes insi pidus, renal abnormalities, psychiatric disorders, and a variety of neurolo gic symptoms: deafness, ataxia, peripheral neuropathy. A gene responsible f or Wolfram Syndrome (WFS1) has been recently identified on chromosome 4p16. 1. Twenty-two Wolfram patients from 16 Spanish families were screened for m utations in the WFS1 coding region by SSCP analysis and direct sequencing. Since WS has been considered a mitochondrial disorder for some time, mitoch ondrial DNA (mtDNA) in these families was also examined. WFS1 mutations wer e detected in 75% of families (12 of 16). One of these mutations, an insert ion of 16 base pairs in exon 4, turned out to be notably frequent in Spanis h pedigrees. As many as 50% of pedigrees with WFS1 mutations harbored this insertion, either in one (33% of cases) or in two chromosomes (67%). Ten ot her mutations were identified: 7 missense changes, 2 deletions, and 1 nonse nse mutation. Only 3 of these changes had been previously described in non- Spanish pedigrees. Large mtDNA rearrangements and LHON point mutations were detected in four and six families, respectively. No correlation could be e stablished between WFS1 gene mutations and specific point mutations or rear rangements in mtDNA. We would suggest first screening for the 16-bp inserti on in exon 4 when a new Spanish WS case is reported. (C) 2001 Academic Pres s.