Evidence suggesting digenic inheritance of waardenburg syndrome type II with ocular albinism

Pei-Wen Chiang, Elaine Spector, Tracy L. McGregor

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 TYR R402Qallele 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.

Original languageEnglish (US)
Pages (from-to)2739-2744
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume149
Issue number12
DOIs
StatePublished - Dec 2009
Externally publishedYes

Fingerprint

Ocular Albinism
Waardenburg Syndrome
Mutation
Pigmentation
Basic Helix-Loop-Helix Transcription Factors
Monophenol Monooxygenase
Melanocytes
Genes
Transcription Factors
Alleles
Phenotype

Keywords

  • MITF
  • OCA1
  • OCA3
  • Ocular albinism
  • Oculocutaneous albinism
  • Pigmentation
  • Waardenburg syndrome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Evidence suggesting digenic inheritance of waardenburg syndrome type II with ocular albinism. / Chiang, Pei-Wen; Spector, Elaine; McGregor, Tracy L.

In: American Journal of Medical Genetics, Part A, Vol. 149, No. 12, 12.2009, p. 2739-2744.

Research output: Contribution to journalArticle

Chiang, Pei-Wen ; Spector, Elaine ; McGregor, Tracy L. / Evidence suggesting digenic inheritance of waardenburg syndrome type II with ocular albinism. In: American Journal of Medical Genetics, Part A. 2009 ; Vol. 149, No. 12. pp. 2739-2744.
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