Homozygosity for piebaldism with a proven KIT mutation resulting in depigmentation of the skin and hair, deafness, developmental delay and autism spectrum disorder

Kilsby, Amanda J.; Cruwys, Michele; Kukendrajah, Chelvi; Russell‐Eggitt, Isabelle; Raglan, Ewa; Rajput, Kaukab; Loshe, Peter; Brady, Angela

doi:10.1097/mcd.0b013e32835e8ce5

Cited by 20 publications

(10 citation statements)

References 6 publications

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“…In humans, KIT mutations can result in the neurocristopathy (a pathology affecting normal neural crest development) piebaldism [MIM 172800], a disorder characterized by areas of skin and hair devoid of melanocytes. Although most of these patients have a heterozygous mutation, deafness has been observed in rare cases of both heterozygous and homozygous mutations (Spritz and Beighton, 1998; Kilsby et al, 2013). We show that KIT is expressed by strial melanocytes in the human fetal cochlea, suggesting that SNHL due to KIT mutations in humans is caused by mechanisms similar to those in mouse Kit mutants.…”

Section: Discussionmentioning

confidence: 99%

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Locher

Groot

Iperen

et al. 2015

Developmental Neurobiology

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Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9–W18) and show the cochlear expression dynamics of key potassium‐regulating proteins. At W12, MITF+/SOX10+/KIT+ neural‐crest‐derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+/K+‐ATPase‐positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1219–1240, 2015

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Section: Discussionmentioning

confidence: 99%

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Locher

Groot

Iperen

et al. 2015

Developmental Neurobiology

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“…KIT mutations have been found in patients featuring ASD symptoms (Kilsby et al, 2013). KIT is a tyrosine kinase receptor (Kasamatsu et al, 2008), which acts as a key developmental regulator in the NC-derived processes of hematopoiesis, melanogenesis, and gametogenesis (Rothschild et al, 2003).…”

Section: Asd and The Genetics Of The Domestication Syndromementioning

confidence: 99%

Language Impairments in ASD Resulting from a Failed Domestication of the Human Brain

2016

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Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders entailing social and cognitive deficits, including marked problems with language. Numerous genes have been associated with ASD, but it is unclear how language deficits arise from gene mutation or dysregulation. It is also unclear why ASD shows such high prevalence within human populations. Interestingly, the emergence of a modern faculty of language has been hypothesized to be linked to changes in the human brain/skull, but also to the process of self-domestication of the human species. It is our intention to show that people with ASD exhibit less marked domesticated traits at the morphological, physiological, and behavioral levels. We also discuss many ASD candidates represented among the genes known to be involved in the “domestication syndrome” (the constellation of traits exhibited by domesticated mammals, which seemingly results from the hypofunction of the neural crest) and among the set of genes involved in language function closely connected to them. Moreover, many of these genes show altered expression profiles in the brain of autists. In addition, some candidates for domestication and language-readiness show the same expression profile in people with ASD and chimps in different brain areas involved in language processing. Similarities regarding the brain oscillatory behavior of these areas can be expected too. We conclude that ASD may represent an abnormal ontogenetic itinerary for the human faculty of language resulting in part from changes in genes important for the “domestication syndrome” and, ultimately, from the normal functioning of the neural crest.

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“…PBT is a rare autosomal dominant genodermatosis caused by mutations in the c-kit proto-oncogene, which encodes the transmembrane receptor tyrosine kinase for mast cell growth factor (MGF, also known as stem cell factor) [9,10,11,12,13,14]. The KIT receptor and its ligand (KITLG) act as crucial factors in the control of physiological and pathological skin pigmentation through the Ras ⁄ mitogen-activated protein kinase (MAPK) signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently Spritz et al [12] described a South African female affected by severe SNHL and PBT carrying a heterozygous missense change (p.R796G) in the KIT gene. Human homozygosity for KIT germline mutations has been reported in a severe multisystem phenotype consisting of hypopigmented skin and hair, blue irides, neurodevelopmental delay, hypotonia, SNHL, anemia, brachycephaly and clinodactyly [13,14]. In view of the uniqueness of the probands’ phenotype and the rarity of neurological manifestations in PBT, we hypothesized the presence of other genetic changes.…”

Section: Discussionmentioning

confidence: 99%

“…Precisely, congenital sensorineural hearing loss (SNHL) is a very common feature in WS and TS patients; conversely, it has been described more rarely in PBT and OCA subjects [4,5,6]. Table 1 synthesizes the clinical and genetic findings of all known neural crest–associated diseases characterized by hypopigmentary congenital disorders [3,4,5,6,7,8,9,10,11,12,13,14,15].…”

Section: Introductionmentioning

confidence: 99%

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Congenital Sensorineural Hearing Loss and Inborn Pigmentary Disorders: First Report of Multilocus Syndrome in Piebaldism

et al. 2019

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Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the neurocristopathies, a group of congenital multisystem disorders caused by an altered development of the neural crest cells, multipotent progenitors of a wide variety of different lineages, including those differentiating into peripheral nervous system glial cells and melanocytes. We report on clinical and genetic findings of two monozygotic twins from a large Albanian family who showed a complex phenotype featured by sensorineural congenital deafness, severe neuropsychiatric impairment, and inborn pigmentary defects of hair and skin. The genetic analyzes identified, in both probands, an unreported co-occurrence of a new heterozygous germline pathogenic variant (c.2484 + 5G > T splicing mutation) in the KIT gene, consistent with the diagnosis of piebaldism, and a heterozygous deletion at chromosome 15q13.3, responsible for the neuropsychiatric impairment. This case represents the first worldwide report of dual locus inherited syndrome in piebald patients affected by a complex auditory-pigmentary multisystem phenotype. Here we also synthesize the clinical and genetic findings of all known neurocristopathies characterized by a hypopigmentary congenital disorder.

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Homozygosity for piebaldism with a proven KIT mutation resulting in depigmentation of the skin and hair, deafness, developmental delay and autism spectrum disorder

Cited by 20 publications

References 6 publications

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Language Impairments in ASD Resulting from a Failed Domestication of the Human Brain

Congenital Sensorineural Hearing Loss and Inborn Pigmentary Disorders: First Report of Multilocus Syndrome in Piebaldism

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