Introduction: Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by the association of early-onset, insulin-dependent diabetes mellitus (DM), diabetes insipidus, deafness, and progressive optic atrophy. The disease is caused by mutations of wfs1 located on 4p16 encoding peptide that is called wolframin. Wolframin is a component of the endoplasmic reticulum (ER) membrane. It is considered that mutant Wolframin might cause increased misfolded and unfolded proteins in ER followed by cell apoptosis. Here, we report a Japanese female patient with DM, deafness, and congenital cataract.
Case report: The patient was admitted to our hospital for poor weight gain and DM. Her growth failure was evident at 3 months old and congenital cataract was noticed at 7 months old. In addition, auditory brainstem response (ABR) test revealed her severe bilateral hearing loss. Her psychomotor development was also delayed. Based on these findings, she was suspected to have WS.
Methods: The wfs1 exon was amplified by PCR and direct sequencing was performed. The functional consequence of the mutant wfs1 identified in this study was analysed using GPR78-luciferase vector in vitro.
Results: Sequence analysis showed a heterozygous 12 bases deletion in exon 8 (c.973_984del12), resulting in three amino acids in-frame deletion. As her parents did not have the deletion, the mutation presumably occurred de novo. In vitro analysis revealed that the mutant wfs1 lost the suppression activity of ER stress response compared with the wild type wfs1, resulting in the increase of ER stress.
Conclusion: We identified a novel non-inactivating mutation of wfs1 in a Japanese patient with WS.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology