A follow-up study of a Chinese family with Waardenburg syndrome type II caused by a truncating mutation of MITF gene

Abstract

Background: Waardenburg syndrome (WS) is a highly clinically and genetically heterogeneous disease. The core disease phenotypes of WS are sensorineuronal hearing loss and pigmentary disturbance, which are usually caused by the absence of neural crest cell-derived melanocytes. At present, four subtypes of WS have been defined, which are caused by seven genes. Waardenburg syndrome type 2 (WS2) is one of the most common forms. Two genes, MITF and SOX10, have been found to be responsible for majority of WS2.

Methods: In this study, we performed a clinical longitudinal follow-up and mutation screening for a Chinese family with Waardenburg syndrome type II.

Results: A diversity of clinical manifestations was observed in this WS2 family. In addition to the congenital hearing loss of most affected family members, progressive hearing loss was also found in some WS2 patients. A nonsense mutation of c.328C>T (p.R110X) in MITF was identified in all affected family members. This mutation results in a truncated MITF protein, which is considered to be a disease-causing mutation.

Conclusion: These findings offer a better understanding of the spectrum of MITF mutations and highlight the necessity of continuous hearing assessment in WS patients.

Keywords: MITF; Waardenburg syndrome; gene mutation; hearing loss.

FIGURE 1

Pedigree of family JX‐WS01 with WS2, and audiograms showing threshold shifts of individual III:2, III:4, IV:2, and IV:3. Progressive hearing loss was found in this family in the period of 13 years of follow‐up. Disconnected circle means that thresholds are undetectable even at the level of the maximal output of audiometer. Y=year; TH=threshold

FIGURE 2

Diverse heterochromia iris in family JX‐WS01. III:2, IV:2, and V:2: brilliant blue iris; IV:3: partial heterochromia iridis; IV:5 and V:3: complete heterochromia iridis

FIGURE 3

Mutational analysis of affected members of family JX‐WS01 and healthy controls. (a) DNA sequence chromatograms showing a heterozygous nonsense mutation of c.328C>T in MITF in patients. This mutation is absent in wild‐type controls. The mutation alters the 110th codon which encodes arginine into a premature termination codon (p.R110X). (b) The schematic illustration of MITF protein. Mutation p.R110X causes MITF to loss three‐quarters of the length of protein sequence, including a basic DNA binding domain, helix‐loop‐helix motif, and a leucine zipper. AD1‐3, transactivation domains; b, basic DNA binding domain; HLH, helix‐loop‐helix motif; LZ, leucine zippedomain