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首页> 美国卫生研究院文献>American Journal of Human Genetics >Allelic Mutations of KITLG Encoding KIT Ligand Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2
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Allelic Mutations of KITLG Encoding KIT Ligand Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2

机译：KITLG的等位基因突变编码KIT配体导致非对称和单侧听力损失和2型Waardenburg综合征

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Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.
机译：连锁分析结合全基因组测序在一个先天性且稳定的非综合征性单侧和非对称性听力损失（NS-UHL / AHL）的大家庭中揭示了KITLG中的杂合性截断突变c.286_303delinsT（p.Ser96Ter）。该突变与NS-UHL / AHL共分离为显性降低的显性。通过用NS-UHL / AHL筛选一组先证者，我们发现了另一个突变c.200_202del（p.His67_Cys68delinsArg）。体外研究表明，在细胞膜上未检测到KITLG的p.His67_Cys68delinsArg跨膜同工型，支持致病性。 KITLG编码KIT受体的配体。另外，建议在黑素细胞发育中，KITLG-KIT信号传导和MITF相互作用。因为MITF中的突变是2型Waardenburg综合征（WS2）的病因，所以我们在可疑WS2影响的先证者中筛选了KITLG。在一个小家族中鉴定出与WS2分离的杂合错义突变，c.310C> G（p.Leu104Val）。体外研究表明，KITLG的p.Leu104Val跨膜同工型与野生型KITLG一样位于细胞膜上。但是，在转染细胞的培养基中，KITLG的p.Leu104Val可溶性同工型减少了，没有检测到可溶性p.His67_Cys68delinsArg和p.Ser96Ter KITLG。这些数据表明，与NS-UHL / AHL相关的KITLG中的突变具有功能丧失作用。我们推测，WS2基础突变并导致膜掺入和KITLG分泌减少的机制是通过显性负性或功能获得性作用发生的。我们的研究揭示了与KITLG相关的不同表型，以前与色素沉着异常有关，因此将改善对具有KITLG变体的个体的遗传咨询。

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