MITF – Waardenburg Syndrome Type 2

Waardenburg syndrome type 2 (WS2) is an autosomal dominant auditory-pigmentary disorder characterised by sensorineural hearing loss and pigmentary abnormalities without dystopia canthorum. The microphthalmia-associated transcription factor gene (MITF) has been established as a major locus for WS2, accounting for ~20% of cases (PMID:9546825). MITF encodes a basic-helix-loop-helix leucine-zipper transcription factor essential for melanocyte development and survival.

Initial linkage to chromosome 3p12.3-p14.1 and direct sequencing in two multiplex families identified canonical splice-site variants c.442-2A>C and c.33+1G>A disrupting MITF transcript processing, establishing causality in multiple unrelated probands (PMID:7874167). Subsequent studies uncovered loss-of-function alleles, including stop-gain and frameshift mutations, confirming an autosomal dominant haploinsufficiency mechanism.

A Chinese Han family exhibited a homozygous missense substitution c.668G>A (p.Arg223His) segregating with classic WS2 features and, in homozygotes, additional megacolon and chronic constipation compatible with WS4, whereas heterozygous carriers had mild pigmentary anomalies alone (PMID:30549420). A longitudinal follow-up in another pedigree revealed the nonsense variant c.328C>T (p.Arg110Ter) in all affected members, underpinning progressive hearing loss and pigmentary disturbance (PMID:33045145).

Genetic screening across cohorts has identified over fifteen distinct MITF variants—including eight truncating alleles and seven missense substitutions—in more than fifty probands from over twenty families (PMID:8659547, PMID:9170159). Recurrent in-frame deletions affecting codon Arg217 (c.643AGA[2] (p.Arg217del)) highlight mutation hotspots and potential founder effects.

Functional assays demonstrate that MITF variants associated with WS2 abrogate DNA-binding capacity and fail to transactivate melanocyte-specific promoters without exhibiting dominant-negative activity, consistent with haploinsufficiency (PMID:8659547, PMID:9170159). Mouse microphthalmia (mi) models recapitulate human phenotypes, further supporting pathogenic mechanisms.

Integration of long-standing genetic and experimental data yields a definitive gene-disease association. Clinical genetic testing for MITF and close audiologic and pigmentary follow-up are recommended for early diagnosis, family counselling, and management of WS2. Key take-home: MITF loss-of-function variants are a primary cause of autosomal dominant WS2 with clear diagnostic and prognostic value.

References

• Nature genetics • 1994 • Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. PMID:7874167
• American journal of human genetics • 1996 • Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A. PMID:8659547
• Pigment cell research • 1997 • Evidence to suggest that expression of MITF induces melanocyte differentiation and haploinsufficiency of MITF causes Waardenburg syndrome type 2A. PMID:9170159
• Clinical dysmorphology • 1998 • Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome). PMID:9546825
• American journal of medical genetics. Part A • 2019 • A homozygous MITF mutation leads to familial Waardenburg syndrome type 4. PMID:30549420
• Molecular genetics & genomic medicine • 2020 • A follow-up study of a Chinese family with Waardenburg syndrome type II caused by a truncating mutation of MITF gene. PMID:33045145

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