Diabetes mellitus (DM) is a common chronic disorder in children. Type1 DM is the most common form of DM and is due to the loss of insulin secretion by autoimmune destruction of pancreatic β-cells. Type2 DM is due to insulin resistance. Maturity Onset Diabetes of the Young is a heterogeneous group of monogenic disorders due to single gene defects. DM and sensorineural deafness (SND) are associated with rare syndromes such as Wolfram syndrome (WS), Rogers syndromes and Mitochondrial DM. WS is an autosomal recessive disorder characterised by diabetes insipidus, DM, optical atrophy and SND, caused by mutations in the WFS1 gene. Rogers syndrome is associated with DM, anaemia, SND and is due to mutations in SLC19A2. Mitochondrial DM (MT-TL1) is associated with SND in more than 60% of cases. The aims of this study were to exclude these known genetic causes of DM and SND and to identify novel genetic mechanisms. PCR, Sanger sequencing, homozygosity mapping (HZM) and exome sequencing was performed on the 5 families’ for the affected and unaffected siblings to identify novel variants. Immunohistochemistry was used to see whether the candidate protein was expressed in the pancreatic and inner ear tissues. This study has identified 3 novel and 1 known mutations in the WFS1 gene. This work expands the molecular spectrum of the WFS1 mutations in WS, with three novel mutations in three unrelated consanguineous families. However, WS should be considered in any patients with DM and SND. The study also identified two novel genes; NOX1 and SSH2, with the former expressed in both the inner ear and the pancreas and the latter only in the ear. This would suggest NOX1 as a potential new gene involved in DM and SND and SSH2 as being one of two mutations that are causing the DM and SND syndrome.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:647275 |
| Date | January 2015 |
| Creators | Sherif, M. M. A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1463447/ |
Page generated in 0.0021 seconds