Endocrine Abstracts

Introduction: Wolfram Syndrome (DIDMOAD) is an autosomal recessive disease caused by mutations in WFS1 gene, resulting in childhood onset diabetes mellitus and optic atrophy. There have been limited functional assays for WFS1 genetic variants. We aimed to investigate WFS1 protein expression in patients and relate this to their genotype and phenotype.

Methods: Nine patients from a regional paediatric centre consented to skin biopsies. Six patients had compound heterozygous nonsense WFS1 variants; one patient (S001) had compound heterozygous nonsense and missense (c.505G>A;p.Glu169Lys) WFS1 variants; and two patients had single heterozygote variants: S002 (c.937C>T;p.His313Tyr plus 6 base-pair duplication in untranslated region) and S007 (c.1153G>A;p.Glu385Lys plus a pathogenic duplication in OPA1 gene).

WFS1 protein levels were measured by Western blotting from fibroblasts derived from patients and commercially available controls. Data was collected on onset of clinical features and disease progression to date

Results: The six patients with compound heterozygous nonsense variants showed no detectable WFS1 protein (‘deficient WFS1 expression’ group). Patient S001, S002 and S007 had 4.1, 52.8 and 47.8% WFS1 protein expression, respectively (‘partial WFS1 expression’ group).

There was a statistically significant difference in the onset of optic atrophy (P=0.02): median age of 11 (10, 14) years in ‘partial WFS1 expression’, compared to 5.5 (4, 8) years in ‘deficient WFS1 expression’.

There was also a clinically significant difference in the degree of visual impairment: ‘partial WFS1 expression’ were either asymptomatic, colour blind or had temporal visual field reduction, compared to ‘deficient WFS1 expression’ who were all registered severely visually impaired; requiring Braille, speech software, or guide dogs.

There was no statistically significant difference in the glycated haemoglobin or insulin requirement between groups.

Conclusion: Residual WFS1 protein expression in patients manifests as later onset of optic atrophy with milder visual impairment. Interestingly, even 4% expression of missense WFS1 variant seems to confer a better ophthalmic phenotype and indicates this variant retains some function.

This suggests the potential protective effects of partial WFS1 protein expression on severity of optic atrophy and opens up avenues for future therapies that may help upregulate partial WFS1 protein expression in Wolfram Syndrome patients and slow down disease progression.