2018
DOI: 10.1038/s41598-018-26818-2
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Abstract: Whole-exome sequencing of samples from affected members of two unrelated families with late-onset non-syndromic hearing loss revealed a novel mutation (c.2090 T > G; NM_017433) in MYO3A. The mutation was confirmed in 36 affected individuals, showing autosomal dominant inheritance. The mutation alters a single residue (L697W or p.Leu697Trp) in the motor domain of the stereocilia protein MYO3A, leading to a reduction in ATPase activity, motility, and an increase in actin affinity. MYO3A-L697W showed reduced filo… Show more

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Cited by 24 publications
(29 citation statements)
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“…A recessive form of HI with pathologic variants in MYO3A has also been reported in a Chinese family ( 33 ). On the other side, variants in MYO3A have been associated with autosomal dominant progressive HI in an African American family ( 34 ) and among individuals presenting HI from two unrelated families from the southeastern region of Brazil ( 35 ). Similar to the present study, variants in MYO15A were found in patients with profound HI from Morocco ( 36 ) and Tunisia ( 37 ), and variants in MYO15A were the most common causes (15·3%) of genetic HI in 61 Egyptian families ( 38 ).…”
Section: Discussionmentioning
confidence: 99%
“…A recessive form of HI with pathologic variants in MYO3A has also been reported in a Chinese family ( 33 ). On the other side, variants in MYO3A have been associated with autosomal dominant progressive HI in an African American family ( 34 ) and among individuals presenting HI from two unrelated families from the southeastern region of Brazil ( 35 ). Similar to the present study, variants in MYO15A were found in patients with profound HI from Morocco ( 36 ) and Tunisia ( 37 ), and variants in MYO15A were the most common causes (15·3%) of genetic HI in 61 Egyptian families ( 38 ).…”
Section: Discussionmentioning
confidence: 99%
“…Many MYO3A hearing loss mutations have been identified via genetic screens, while two dominant mutations, G488E and L697W, have been studied in depth ( Grati et al, 2016 ; Dantas et al, 2018 ). G488E was shown to reduce ATPase activity but increase the in vitro motility of MYO3A ( Grati et al, 2016 ).…”
Section: The Myosin Superfamilymentioning
confidence: 99%
“…We speculated that the G488E mutant may be unable to walk to the filopodia tips because of its disrupted ATPase cycle and or duty ratio, but in the stereocilia interactions with other binding partners may allow the mutant to translocate to the tips (e.g., as a complex with endogenous WT MYO3A). The L697W mutant was found to decrease both ATPase activity and in vitro motility, however, it did not have a defect in tip localization in COS-7 cells ( Dantas et al, 2018 ). Interestingly, L697W was able to outcompete WT MYO3A for localization to protrusion tips in the presence of ESPN-1, while filopodia were overall shorter and fewer in number in the presence of the mutant.…”
Section: The Myosin Superfamilymentioning
confidence: 99%
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“…Essas análises revelaram aumento da concentração e do tempo de permanência da proteína mutada nas extremidades dos estereocílios, deslocando a proteína selvagem. Esses e outros achados do estudo levaram os autores a postular que o mecanismo molecular que leva à herança dominante da perda auditiva nas famílias com a mutação c.2090T>G p.Leu697Trp no gene MYO3A é o efeito dominante negativo (Dantas et al, 2018).…”
Section: Genética Das Perdas Auditivasunclassified