Homozygous intronic <i><scp>MITF</scp></i> mutation causes severe Waardenburg syndrome type 2A

Rauschendorf, Marc-Alexander; Zimmer, Andreas; Laut, Astrid; Demmer, Philipp; Rösler, Bernd; Happle, Rudolf; Sartori, S; Fischer, Judith

doi:10.1111/pcmr.12733

Cited by 11 publications

(7 citation statements)

References 16 publications

(13 reference statements)

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“…There are also compound heterozygotes, as demonstrated recently in individuals with a novel syndrome called COMMAD (coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness), depicted in Figure 1B (George et al 2016). Unlike in many Mitf mutant mice, however, human phenotypes are seen in heterozygous individuals, and there is only one report of a homozygous WSIIa individual (Rauschendorf et al 2019). Most intriguing is the observation that one particular germline mutation has an increased susceptibility to develop melanoma and renal cell carcinoma.…”

Section: Microphthalmia-associated Transcription Factor (Mitf) Geneticsmentioning

confidence: 91%

MITF—the first 25 years

2019

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Section: Microphthalmia-associated Transcription Factor (Mitf) Geneticsmentioning

confidence: 91%

MITF—the first 25 years

2019

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“…c MITF mutations found in melanoma (blue, on top) and in pigment deficiency syndromes (WS2A and TS patients, red, bottom) (adapted from [37] (See figure on next page.) a b c more severe WS2A phenotype [135]. Another homozygous mutation (p.R223H) leads to a classic WS with persistent chronic constipation after the neonatal period, a symptom suggestive of Waardenburg syndrome type 4 (WS4), also known as Waardenburg-Shah syndrome [123,124].…”

Section: Diseases Associated With Mitfmentioning

confidence: 99%

The underestimated role of the microphthalmia-associated transcription factor (MiTF) in normal and pathological haematopoiesis

Oppezzo

Rosselli

2021

Cell Biosci

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Haematopoiesis, the process by which a restrained population of stem cells terminally differentiates into specific types of blood cells, depends on the tightly regulated temporospatial activity of several transcription factors (TFs). The deregulation of their activity or expression is a main cause of pathological haematopoiesis, leading to bone marrow failure (BMF), anaemia and leukaemia. TFs can be induced and/or activated by different stimuli, to which they respond by regulating the expression of genes and gene networks. Most TFs are highly pleiotropic; i.e., they are capable of influencing two or more apparently unrelated phenotypic traits, and the action of a single TF in a specific setting often depends on its interaction with other TFs and signalling pathway components. The microphthalmia-associated TF (MiTF) is a prototype TF in multiple situations. MiTF has been described extensively as a key regulator of melanocyte and melanoma development because it acts mainly as an oncogene. Mitf-mutated mice show a plethora of pleiotropic phenotypes, such as microphthalmia, deafness, abnormal pigmentation, retinal degeneration, reduced mast cell numbers and osteopetrosis, revealing a greater requirement for MiTF activity in cells and tissue. A growing amount of evidence has led to the delineation of key roles for MiTF in haematopoiesis and/or in cells of haematopoietic origin, including haematopoietic stem cells, mast cells, NK cells, basophiles, B cells and osteoclasts. This review summarizes several roles of MiTF in cells of the haematopoietic system and how MiTFs can impact BM development.

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“…Inter-and intrafamilial variability in the expression of symptoms have also been observed. In some cases of WS, biallelic mutations have also been reported suggesting an autosomal recessive inheritance [8,[21][22][23][24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Frameshift variant in MITF gene in a large family with Waardenburg syndrome type II and a co-segregation of a C2orf74 variant

et al. 2021

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Waardenburg syndrome (WS) is a hereditary disorder affecting the auditory system and pigmentation of hair, eyes, and skin. Different variants of the disease exist with the involvement of mutation in six genes. The aim of the study is to identify the genetic defects underlying Waardenburg syndrome in a large family with multiple affected individuals. Here, in this study, we recruited a large family with eleven affected individuals segregating WS type 2. We performed whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach. Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (c.965delA) in the MITF gene. Moreover, a rare heterozygous, missense damaging variant (c.101T>G; p.Val34Gly) in the C2orf74 has also been identified. The C2orf74 is an uncharacterized gene present in the linked region detected by DominantMapper. Variants in MITF and C2orf74 follows autosomal dominant segregation with the phenotype, however, the variant in C2orf74 is incompletely penetrant. We proposed a digenic inheritance of variants as an underlying cause of WS2 in this family.

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Homozygous intronic MITF mutation causes severe Waardenburg syndrome type 2A

Cited by 11 publications

References 16 publications

MITF—the first 25 years

MITF—the first 25 years

The underestimated role of the microphthalmia-associated transcription factor (MiTF) in normal and pathological haematopoiesis

Frameshift variant in MITF gene in a large family with Waardenburg syndrome type II and a co-segregation of a C2orf74 variant

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