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Mitf point mutation. (a) Co-segregation of SSC polymorphism and Wh allele in an intercross between two Wh/+, E/e heterozygotes. Only the single-stranded (upper) portion of the autoradiogram is shown. The position of wild-type (+) and mutant (Wh) conformers is indicated. For comparison, PCR fragments from wild-type and mutant progenitors used for DNA sequence analysis are shown to the right of the pedigree. A heterozygous pattern was visible in the paternal lane upon longer exposure. The extension mutation (e) segregates independently from the Mitf polymorphism. *, e/e genotype; open symbols, wild-type; half-filled symbols, Wh heterozygote; filled symbols, anophthalmic white hamster. (b) Portion of the sequencing gels for genomic PCR clones showing the Wh nonsense mutation (Trp→Stop). (c) Diagram comparing rodent and human bHLHzip regions and showing the Wh mutation. The mouse and hamster (accession No. AF020900) sequences are identical. The two amino acid differences in the human bHLHzip region (7) are overlined and the four heptad repeats in the leucine zipper are indicated (Ρ). The amino acids are numbered according to the mouse (13) and human (7) polypeptides, as the hamster start codon has not been identified. The mouse cloudy-eyes allele (ce) 26 and two human WS2 nonsense mutations (11) are included for comparison. Wh and ce terminate at positions 241 and 263, respectively. The human mutations flank the position of Wh.
Source publication
Mutations in MITF (microphthalmia transcription factor) cause Waardenburg syndrome type 2 (WS2A) in humans, an autosomal dominant disorder consisting of deafness and hypopigmentation. Phenotypes vary significantly within WS2 pedigrees, and there is generally no correlation between the predicted biochemical properties of mutant MITF proteins and dis...
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Purpose: To assess the choroidal thickness in differently pigmented areas of the fundus in a 46-year-old female with Waardenburg syndrome. OCT-1 Atlantis) and compared between the pigmented and hypopigment-ed areas within the same eye and between the two eyes. Yamini Attiku 1 Results: Best corrected visual acuity (BCVA) was 20/20 in both eyes. The...
Background
It is important that multiple genetic diagnoses are not missed. This case report describes the clinical features and management of a patient with co-inheritance of Waardenburg syndrome type 4 or Waardenburg-Shah syndrome, an extremely rare disease, and homozygous sickle cell disease not uncommon in the Caribbean. This case is unusual as...
MITF is a known gene underlying autosomal dominant hearing loss, Waardenburg syndrome (WS). Biallelic MITF mutations have been found associated with a rare hearing loss syndrome consisting eye abnormalities and albinism; and a more severe type of WS whose heterozygous parents were affected with classic WS in both cases. The aims of this study were...
Citations
... Mutations in a gene can account for different types and characteristics of WS. In animal models, mutations in MITF homologues are also responsible for the microphthalmia phenotypes of the mibA rat mutant, the anophthalmic white and Wh V203 hamster mutants and the nacre and nac W2 zebrafish mutants [19][20][21] . However, in humans, the majority number of mutations in MITF cause more moderate phenotypes with WS2, and most of mutations are expected to be located in exon 7 and 8, which correspond to the b-HLH-Zip motifs [5] , including the mutation in this study. ...
Aim:
To reveal a novel MITF gene mutation in Waardenburg syndrome (WS), which is an autosomal dominant inherited neurogenic disorder that consists of various degrees of sensorineural deafness and pigmentary abnormalities in the eyes, hair and skin.
Methods:
The genetic analysis of the Chinese family was conducted by whole-exome sequencing, then the results were confirmed by Sanger sequencing.
Results:
WS is classified into type I to IV, which are identified by the W index, clinical characteristics and additional features. The MITF gene mostly accounts for WS type II. In this study, a de novo heterozygous mutation in the MITF gene, c.638A>G in exon 7, was identified in the patient diagnosed with WS type I features, as the W index was 2.17 (over 2.10), with dystrophia canthorum, congenital bilateral profound hearing loss, bilateral heterochromia irides, premature greying of the hair, and excessive freckling on the face at birth. She also underwent refractive errors and esotropia, reduced pigmentation of the choroid and visible choroid vessels. The mutation was not found in previous studies or mutation databases.
Conclusion:
The novel mutation in the MITF gene, which altered the protein in amino acids 213 from the glutamic acid to glycine, is the genetic pathological cause for WS features in the patient. Those characteristics of this family revealed a novel genetic heterogeneity of MITF in WS, which expanded the database of MITF mutations and offered a possible in correcting the W index value of WS in distinct ethnicities. Moreover, ocular symptoms should be emphasized in all types of WS patients.
... The incidence of WS is estimated as 1 on 42,000 among Caucasian populations, or 2-5% among patients with congenital deafness, and 0.9-2.8% among adults with hearing impairment [2,3,[5][6][7]. Four types of WS differing in phenotypic characteristics are now described. The WS type 1 (MIM 193,500) and the WS type 2 (MIM 193,510) share similar main symptoms (pigmentation and hearing abnormalities). ...
... However, the patients with WS type 1 additionally have a dystopia canthorum (lateral displacement of the inner canthi of the eyes with the normal interpupillary distance) while this feature is absent in patients with WS type 2. The WS type 3 or Waardenburg-Klein syndrome (MIM 148,820) includes upper limbs anomalies in addition to main WS symptoms. The WS type 4 (also known as Waardenburg-Shah syndrome, MIM 277,580) has main WS features accompanied by Hirschprung disease [1][2][3][4][5][6][7][8][9][10][11][12][13]. Detailed and correct characterisation of identified WS cases is very important since phenotypical features of the WS often vary even among members of one family [1][2][3][4][5][6][7][8][9][10][11][12][13]. ...
... The WS type 4 (also known as Waardenburg-Shah syndrome, MIM 277,580) has main WS features accompanied by Hirschprung disease [1][2][3][4][5][6][7][8][9][10][11][12][13]. Detailed and correct characterisation of identified WS cases is very important since phenotypical features of the WS often vary even among members of one family [1][2][3][4][5][6][7][8][9][10][11][12][13]. Mutations in the РАХ3, MITF, SOX10 and SNAI2 genes are known as main causes for WS [9,10]. ...
Waardenburg syndrome (WS) is an orphan genetic disease with autosomal dominant pattern of inheritance characterised by varying degrees of hearing loss accompanied by skin, hair and iris pigmentation abnormalities. Four types of WS differing in phenotypic characteristics are now described. We performed a Sanger sequencing of coding regions of genes PAX3, MITF, SOX10 and SNAI2 in the patient with WS from a Yakut family living in the Sakha Republic. No changes were found in the PAX3, SOX10 and SNAI2 coding regions while a previously reported heterozygous transition c.772C>T (p.Arg259*) in exon 8 of the MITF gene was found in this patient. This patient presents rare phenotype of WS type 2: congenital unilateral hearing loss, unilateral heterochromia of irises, and absence of skin/hair depigmentation and dystopia canthorum. Audiological variability in WS type 2, caused by the c.772C>T (p.Arg259*) variant in the MITF gene, outlines the importance of molecular analysis and careful genotype–phenotype comparisons in order to optimally inform patients about the risk of hearing loss. The results of this study confirm the association of pathogenic variants in the MITF gene with WS type 2 and expanded data on the variability of audiological features of the WS.
... Other loss-of-pigment phenotypes resemble the grey-morph pattern, but to a lesser extent. For example, four subtypes of Waardenburg syndrome have been described and are known to be caused by mutations in PAX3 (chromosome 2q35), [53][54][55][56], MITF (chromosome 3p14-p13) [57][58], SOX10 (chromosome 22q13.1) [59][60][61], SNAI2 (chromosome 8q11.21) ...
Southern right whales (SRWs, Eubalena australis) are polymorphic for an X-linked pigmentation pattern known as grey morphism. Most SRWs have completely black skin with white patches on their bellies and occasionally on their backs; these patches remain white as the whale ages. Grey morphs (previously referred to as partial albinos) appear mostly white at birth, with a splattering of rounded black marks; but as the whales age, the white skin gradually changes to a brownish grey color. The cellular and developmental bases of grey morphism are not understood. Here we describe cellular and ultrastructural features of grey-morph skin in relation to that of normal, wild-type skin. Melanocytes were identified histologically and counted, and melanosomes were measured using transmission electron microscopy. Grey-morph skin had fewer melanocytes when compared to wild-type skin, suggesting reduced melanocyte survival, migration, or proliferation in these whales. Grey-morph melanocytes had smaller melanosomes relative to wild-type skin, normal transport of melanosomes to surrounding keratinocytes, and normal localization of melanin granules above the keratinocyte nuclei. These findings indicate that SRW grey-morph pigmentation patterns are caused by reduced numbers of melanocytes in the skin, as well as by reduced amounts of melanin production and/or reduced sizes of mature melanosomes. Grey morphism is distinct from piebaldism and albinism found in other species, which are genetic pigmentation conditions resulting from the local absence of melanocytes, or the inability to synthesize melanin, respectively.
... WS incidence is 1/212,000 (2), but due to clinical variability of the syndrome (3) it is speculated that the actual population incidence is 1/42,000. Estimates suggest that the syndrome is found in approximately 2-5% of all congenitally deaf persons, and in 0.9-2.8% of the deaf population (4)(5)(6)(7)(8). ...
Waardenburg syndrome (WS) is a rare genetic disorder characterized by hearing loss (HL) and pigment disturbances of hair, skin and iris. Classifications exist based on phenotype and genotype. The auditory phenotype is inconsistently reported among the different Waardenburg types and causal genes, urging the need for an up-to-date literature overview on this particular topic. We performed a systematic review in search for articles describing auditory features in WS patients along with the associated genotype. Prevalences of HL were calculated and correlated with the different types and genes of WS. Seventy-three articles were included, describing 417 individual patients. HL was found in 71.0% and was predominantly bilateral and sensorineural. Prevalence of HL among the different clinical types significantly differed (WS1: 52.3%, WS2: 91.6%, WS3: 57.1%, WS4: 83.5%). Mutations in SOX10 (96.5%), MITF (89.6%) and SNAI2 (100%) are more frequently associated with hearing impairment than other mutations. Of interest, the distinct disease-causing genes are able to better predict the auditory phenotype compared with different clinical types of WS. Consequently, it is important to confirm the clinical diagnosis of WS with molecular analysis in order to optimally inform patients about the risk of HL.
... The deaf white phenotype has been reported in multiple species, including the mouse (Chabot et al., 1988;Ruan et al., 2005), dog (Hudson & Ruben, 1962;Clark et al., 2006), mink (Hilding et al., 1967), horse (Haase et al., 2007(Haase et al., , 2009, rat (Tsujimura et al., 1991), Syrian hamster (Hodgkinson et al., 1998), alpaca (Gauly et al., 2005), and human (Beighton et al., 1991). Such conditions are distinct from albinism, though the absence of pigment can often pervade the whole body. ...
Synaptic function and neuronal organization in the auditory system has been shown to be reactive and malleable to experience. In this regard, deafness has important implications for auditory processing. Although the general blueprint for auditory circuits appears to be established before the onset of hearing, reduced auditory stimulation during postnatal development produces definable pathologic effects on the structural and functional features of synapses, cells, and pathways. Studying these congenital effects can be accomplished in a number of experimental models, but one of the most reliable is that of the deaf white cat. The deaf white cat is a known model of a cochleosaccular degeneration resembling the Scheibe deformity observed in humans. This chapter reviews our current understanding of auditory pathologies consequent to congenital deafness, highlighting observations made in the deaf white cat model. Most significantly, the restorative effects of electrical stimulation on the auditory system by way of cochlear implantation are presented. The available data demonstrate that synaptic organization in the auditory system is highly plastic to environmental influences.
... 5,6 The white, deaf phenotype has been reported in multiple species, including the mouse, dog, mink, horse, rat, Syrian hamster, alpaca, and human. [7][8][9][10][11][12][13][14][15][16][17][18][19] Type 2 Waardenburg syndrome most closely describes the phenotype in humans with distinctive hypopigmentation of skin and hair and congenital cochleosaccule dysplasia that resembles the Scheibe deformity. Investigation of the genetic basis for distinctive coat color phenotypes represent some of the earliest mapped and characterized genetic mutations. ...
Cats have among the best hearing of all mammals in that they are extremely sensitive to a broad range of frequencies. The ear is a highly complex structure that is delicately balanced in terms of its biochemistry, types of receptors, ion channels, mechanical properties, and cellular organization. Sensorineural deafness is caused by "flawed" genes that are inherited from one or both parents. Hearing loss can also be acquired as a result of noise trauma from industrialized environment, viral infection, or blunt trauma. To date, it is not practical to intervene and attempt to correct these forms of deafness in cats.
... Mutations in this gene cause defects in melanocytes, the retinal pigmented epithelium, mast cells and osteoclasts (Steingrímsson et al. 2004;Levy et al. 2006). In particular, mutations having a wide range of effects on coat colour, from moderate spotting to complete absence of pigmentation, have been reported in mice (Steingrímsson et al. 2004;Levy et al. 2006), rat , Syrian hamster (Hodgkinson et al. 1998;Graw et al. 2003), dogs (Rothschild et al. 2006;Karlsson et al. 2007) and Japanese quail (Minvielle et al. 2010). In humans, MITF gene mutations are responsible for Waardenburg syndrome type 2A (Tassabehji et al. 1994;Nobukuni et al. 1996). ...
Candidate gene analysis, quantitative trait locus mapping in outbreed and experimental cross-populations and a genomewide association study in Holstein have reported that a few chromosome regions contribute to great variability in the degree of white/black spotting in cattle. In particular, an important region affecting this trait was localized on bovine chromosome 22 in the region containing the microphthalmia-associated transcription factor (MITF) gene. We sequenced a total of 7258 bp of the MITF gene in 40 cattle of different breeds, including 20 animals from spotted breeds (10 Italian Holstein and 10 Italian Simmental) and 20 animals from solid coloured breeds (10 Italian Brown and 10 Reggiana), and identified 17 single nucleotide polymorphisms (SNPs). The allele frequencies of one polymorphism (g.32386957A>T) were clearly different between spotted (A = 0.875; T = 0.125) and non-spotted breeds (A = 0.125; T = 0.875) (P = 8.2E-12). This result was confirmed by genotyping additional animals of these four breeds (P < 1.0E-20). A total of 21 different haplotypes were inferred from the sequenced animals. Considering similarities among haplotypes, spotted and non-spotted groups of cattle showed significant differences in their haplotype distribution (P = 0.001), which was further supported by the analysis of molecular variance (amova) of two genotyped SNPs in an enlarged sample of cattle. Variability in the MITF gene clearly explained the differences between spotted and non-spotted phenotypes but, at the same time, it is evident that this gene is not the only genetic factor determining piebaldism in Italian Holstein and Italian Simmental cattle breeds.
... Mutations in the MITF gene cause one type of the deafness/pigmentation disorder Waardenburg syndrome in humans, and over 20 alleles at the mouse Mitf locus comprise a complex series of coat color, eye development, osteoclast and mast cell phenotypes. MITF mutations have been described in several other vertebrates, including rat , hamster (Hodgkinson, et al. 1998), quail (Mochii, et al. 1998), and zebrafish (Lister, et al. 1999). In zebrafish, null alleles of the MITF ortholog mitfa result in a complete absence of neural crest-derived melanocytes as well as earlier markers of melanoblast specification including dopachrome tautomerase (dct) and the receptor tyrosine kinase kit (Lister, et al. 1999), but spare the retinal pigment epithelium. ...
The mitfa gene encodes a zebrafish ortholog of the microphthalmia-associated transcription factor (Mitf) which, like its counterparts in other species, is absolutely required for development of neural crest melanocytes. In order to evaluate mitfa's role in different stages of melanocyte development, we have identified hypomorphic alleles of mitfa, including two alleles that are temperature-sensitive for melanocyte development. Molecular analysis revealed that the mitf(fh53)ts results from a single base pair change producing an asparagine to tyrosine amino acid substitution in the DNA-binding domain, and the mitfa(vc7)ts allele is a mutation in a splice donor site that reduces the level of correctly-spliced transcripts. Splicing in the mitfa(vc7) allele does not itself appear to be temperature-dependent. A third, hypomorphic allele, mitfa(z25) results in an isoleucine to phenylalanine substitution in the first helix domain of the protein. Temperature upshift experiments with mitfa(fh53)ts show that mitfa is required at several stages of melanocyte differentiation, including for expression of the early melanoblast marker dct, again for progression from dct expression to differentiation, and again for maintenance of dendritic form following differentiation. mitfa(fh53)ts mutants recover melanocytes within 2-3days when downshifted at all stages of larval development. However, when melanocyte stem cells (MSCs) are ablated by early treatment with the erbB3 inhibitor AG1478, melanocyte recovery is lost by 48 h. This result indicates first that the MSC is established at the restrictive temperature, and that melanoblasts die or lose the ability to recover after being held at the restrictive temperature for approximately one day.
... Also, to date, all other known microphthalmia alleles in mice, by my current count 36, have mutations in Mitf. Furthermore, alterations in the homologs in other species including zebrafish (Lister et al., 1999), quail (Mochii et al., 1998), rat (Opdecamp et al., 1998; Weilbaecher et al., 1998), hamster (Hodgkinson et al., 1998), dog (Karlsson et al., 2007), and man (Tassabehji et al., 1994) are also associated with pigmentary phenotypes, and, in mammals, may lead to deafness (in humans called Waardenburg syndrome IIa). Moreover, the gene is expressed in the cells affected (Opdecamp et al., 1997; Nakayama et al., 1998), including developing and adult melanocytes, developing retinal pigment epithelium cells, mast cells, and osteoclasts, although it is also found in many other cell types that do not show overt phenotypes in Mitf mutants. ...
The history of the discovery of the microphthalmia locus and its gene, now called Mitf, is a testament to the triumph of serendipity. Although the first microphthalmia mutation was discovered among the descendants of a mouse that was irradiated for the purpose of mutagenesis, the mutation most likely was not radiation induced but occurred spontaneously in one of the parents of a later breeding. Although Mitf might eventually have been identified by other molecular genetic techniques, it was first cloned from a chance transgene insertion at the microphthalmia locus. And although Mitf was found to encode a member of a well-known transcription factor family, its analysis might still be in its infancy had Mitf not turned out to be of crucial importance for the physiology and pathology of many distinct organs, including eye, ear, immune system, bone, and skin, and in particular for melanoma. In fact, near seven decades of Mitf research have led to many insights about development, function, degeneration, and malignancies of a number of specific cell types, and it is hoped that these insights will one day lead to therapies benefitting those afflicted with diseases originating in these cell types.
... In vertebrates, Mitf is expressed in melanoblasts and melanin-containing melanocytes (called melanophores in fish, amphibia, and reptiles) and RPE cells (30,(39)(40)(41). This is not to say that Mitf is only found in pigment cells. ...
... MITF-TFE proteins, therefore, do not seem to follow the rationale of regulation by heterodimerization that is seen with the MYC/MAD/MAX group of bHLH-LZ proteins or the myogenic MYOD group of bHLH proteins. This is surprising, because MITF, like these other proteins, also links cell proliferation with cell differentiation (see page 41). ...
