Phenotype-genotype correlations in a series of wolfram syndrome families.
OBJECTIVE
Wolfram syndrome is an extremely rare autosomal-recessive disorder that predisposes the development of type 1 diabetes in association with progressive optic atrophy. The genetic basis of this disease has been shown to be due to mutations in the WFS1 gene. The WFS1 gene encodes a novel transmembrane protein called wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic beta-cells and neurons. Genotype-phenotype correlations in this syndrome are becoming apparent and may help in explaining some of the variable characteristics observed in this disease.


METHODS
In this report, we have studied 13 patients with Wolfram syndrome from nine families to further define the relationship between mutation site and type with specific disease characteristics.


RESULTS
A severe phenotype was seen in patients with mutations in exon 4 and with a large deletion encompassing most of exon 8. In total, nine novel mutations were identified as well as three new silent polymorphisms.


CONCLUSIONS
Similar to all other mutation reports, most causative changes identified in the WFS1 gene occurred in exon 8, and only one was identified outside this region in exon 4.
John Hunter Children's Hospital, University of Newcastle and the Hunter Medical Research Institute, New South Wales, Australia.
Casey J A
CJ
Smith
Patricia A
PA
Crock
Bruce R
BR
King
Cliff J
CJ
Meldrum
Rodney J
RJ
Scott
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D003920:Diabetes Mellitus / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D017384:Sequence Deletion; D014929:Wolfram Syndrome / Q000235:genetics*
D008565:Membrane Proteins; C114987:wolframin protein; D004247:DNA