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Keywords:

  • oculocutaneous albinism;
  • OCA1;
  • OCA3;
  • pigmentation;
  • Waardenburg syndrome;
  • MITF;
  • ocular albinism

Abstract

Waardenburg syndrome (WS) is a series of auditory–pigmentary disorders inherited in an autosomal dominant manner. In most patients, WS2 results from mutations in the MITF gene. MITF encodes a basic helix-loop-helix transcription factor that activates transcription of tyrosinase and other melanocyte proteins. The clinical presentation of WS is highly variable, and we believe that Tietz syndrome and WS2 with ocular albinism (OA) are likely two variations of WS2 due to the presence of modifiers. One family with a molecular diagnosis of WS2 co-segregating with OA has previously been reported. A digenic mutation mechanism including both a MITF mutation and the TYRR402Q hypomorphic allele was proposed to be the cause of OA in this family. Here, we present a second WS2 family with OA and provide evidence suggesting the TYRR402Q allele does not cause OA in this family. We hypothesize the presence of a novel OCA3 mutation together with the MITF del p.R217 mutation account for the OA phenotype in this family. Since MITF is a transcription factor for pigmentation genes, a mutation in MITF plus a heterozygous mutation in OCA3 together provide an adverse effect crossing a quantitative threshold; therefore, WS2 with OA occurs. We have hypothesized previously that the clinical spectrum and mutation mechanism of OCA depend on the pigmentation threshold of an affected individual. This unique family has provided further evidence supporting this hypothesis. We suggest that by studying OCA patients alongside WS patients with various pigmentation profiles we can facilitate further understanding of the pigmentation pathway. © 2009 Wiley-Liss, Inc.