Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes

Abstract

The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.

A Novel Pathogenic Variant in the MITF Gene Segregating with a Unique Spectrum of Ocular Findings in an Extended Iranian Waardenburg Syndrome Kindred

“…Nystagmus has been also reported with SOX10 mutations [Pingault et al, 2000]. Strabismus and amblyopia have been previously reported to be associated with MITF mutations [Léger et al, 2012].…”

“…Léger et al [2012] found a high rate (40%) of ocular abnormalities in their studied population with MITF basic domain mutations, leading to the possibility that they could be more frequently or specifically associated with mutations of this domain. However, it could not be applied to our study since the variant we found here, p.R293X, is not located within the basic domain.…”

Homozygous intronic MITF mutation causes severe Waardenburg syndrome type 2A

“…Individual III1 (index' sister) showed no freckling yet. We cannot rule out that the observed facial freckles are part of the phenotype, as previously proposed by Léger et al (2012) for WS2. Notably, none of the other family members presented large pigmented macules as noted in the propositus.…”

“…Notably, none of the other family members presented large pigmented macules as noted in the propositus. Although patches of hyperpigmented skin have previously been described as part of a WS phenotype (Léger et al, 2012;Ogawa, Kono, & Akiyama, 2017), we believe it is unlikely that the pigmented macules of the propositus (III2) represent true hyperpigmented café-au-lait macules (CALMs). In our view, these pigmented macules represent essentially normal skin pigmentation.…”

Pigmented macules in Waardenburg syndrome type 2 due to KITLG mutation

“…In WS, café-au-lait and large pigmented macules are rare. Our literature search of 262 genetically defined families with WS or related diseases found only three WS families with these phenotypes (Table S2): the previous case with KITLG mutation, a WS2 family with MITF mutation (Leger et al, 2012), and a WS4 patient with SOX10 mutation (Pingault et al, 2014). Additionally, in a family with Yemenite deaf-blind hypopigmentation syndrome, which is a WS-related syndrome with severe ocular deformity, caféau-lait spots were associated with a SOX10 mutation (Bondurand et al, 1999).…”