MITF – Waardenburg syndrome type 2A

Waardenburg syndrome type 2A (WS2A) is an autosomal dominant auditory–pigmentary disorder characterized by congenital sensorineural hearing loss and patches of skin, hair, and iris hypopigmentation. WS2A and Tietz syndrome are allelic conditions caused by heterozygous mutations in MITF, the microphthalmia-associated transcription factor, which encodes a basic helix–loop–helix leucine zipper regulator of melanocyte development and survival.

Genetic evidence for MITF in WS2A includes at least 11 unrelated probands from seven families showing segregation of heterozygous MITF variants with disease in an autosomal dominant pattern ([PMID:8589691]; [PMID:8659547]; [PMID:27604145]). In one pedigree, a missense c.648A>C (p.Arg216Ser) variant co-segregated with WS2A features across multiple affected relatives ([PMID:27604145]). Additional isolated cases carry de novo truncating alleles such as c.1183_1184insG (p.Ser395CysfsTer?).

The variant spectrum comprises missense substitutions within the bHLHZip domain (e.g. c.648A>C (p.Arg216Ser)), truncating frameshifts and nonsense alleles (e.g. c.1183_1184insG (p.Ser395CysfsTer?) and p.Arg259Ter), and small indels affecting splicing. Functional assays of at least 24 MITF mutations demonstrate that most WS2A-associated variants disrupt DNA binding and transcriptional activation of melanocyte-specific promoters ([PMID:23787126]).

Experimental studies reveal a loss-of-function mechanism via haploinsufficiency: truncated MITF proteins lack essential HLHZip structure, lose tyrosinase promoter transactivation, and do not exert dominant-negative effects on wild-type MITF ([PMID:8659547]). Reporter assays confirm absence of DNA-binding activity and failure to activate pigmentation gene expression in vitro.

Some variants, notably p.Ser298Pro, retain normal DNA binding and transactivation capacity, suggesting that not all MITF changes are pathogenic and highlighting the need for functional assessment of novel missense alterations ([PMID:23787126]).

Overall, the evidence supports a Strong gene–disease association for MITF and WS2A. Genetic testing for heterozygous MITF loss-of-function variants is clinically informative for diagnosis and family counseling. Haploinsufficiency underlies WS2A pathogenesis and functional assays are critical for variant classification.

References

• Human molecular genetics • 1995 • The mutational spectrum in Waardenburg syndrome PMID:8589691
• 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
• American journal of medical genetics. Part A • 2016 • Tietz/Waardenburg type 2A syndrome associated with posterior microphthalmos in two unrelated patients with novel MITF gene mutations. PMID:27604145
• Human molecular genetics • 2013 • MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. PMID:23787126

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