Biallelic loss-of-function variants in the centriolar protein CCP110 leads to a ciliopathy-like phenotype(s)

IF 1.6 4区 医学 Q3 GENETICS & HEREDITY
Hisato Suzuki , Yukako Muramatsu , Fuyuki Miya , Hideyuki Asada , Mamiko Yamada , Gen Nishimura , Kenjiro Kosaki , Toshiki Takenouchi
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引用次数: 0

Abstract

CCP110 (centriolar coiled coil protein 110, also known as CP110) is one of the essential proteins localized in the centrosome that plays critical roles in the regulation of the cell cycle and also in the initiation of ciliogenesis. So far, no human congenital disorders have been identified to be associated with pathogenic variants of CCP110. Mice with biallelic loss-of-function variants of Ccp110 (Ccp110−/−) are known to manifest multiple organ defects, including a small body size, polydactyly, omphalocele, congenital heart defects, cleft palate, short ribs, and a small thoracic cage, a pattern of abnormalities closely resembling that in "ciliopathies" in humans. Herein, we report a 7-month-old male infant who presented with growth failure and skeletal abnormalities, including a narrow thorax and severe brachydactyly. Trio exome analysis of the genomic DNA of the patient and his parents showed that the patient was a compound heterozygote for truncating variants of CCP110, including a frameshift variant NM_001323572.2:c.856_857del, p.(Val286Leufs*5) inherited from the father, and a nonsense variant NM_001323572.2:c.1129C>T, p.(Arg377*) inherited from the mother. The strikingly similar pattern of malformations between Ccp110−/− mice and the 7-month-old male infant reported herein carrying unequivocal truncating CCP110 variants strongly supports the contention that CCP110 is a novel disease-causative gene.

中心极蛋白 CCP110 的双叶功能缺失变体会导致纤毛症样表型。
CCP110(中心极盘卷蛋白 110,又称 CP110)是定位于中心体的重要蛋白之一,在细胞周期调控和纤毛生成的启动过程中发挥着关键作用。迄今为止,尚未发现人类先天性疾病与 CCP110 的致病变体有关。已知 Ccp110 双倍功能缺失变体(Ccp110-/-)小鼠表现出多种器官缺陷,包括体型小、多指畸形、脐畸形、先天性心脏缺陷、腭裂、肋骨短和胸廓小,其异常模式与人类 "纤毛虫病 "非常相似。在此,我们报告了一名 7 个月大的男婴,他出现生长发育迟缓和骨骼畸形,包括胸廓狭窄和严重的肱骨发育不良。对患者及其父母的基因组 DNA 进行的三重外显子组分析表明,患者是 CCP110 截断变异的复合杂合子,包括从父亲那里遗传的框架移位变异 NM_001323572.2:c.856_857del,p.(Val286Leufs*5)和从母亲那里遗传的无义变异 NM_001323572.2:c.1129C>T,p.(Arg377*)。Ccp110-/- 小鼠与本文报告的携带明确截短 CCP110 变体的 7 个月大男婴的畸形模式惊人地相似,这有力地支持了 CCP110 是一种新型致病基因的论点。
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来源期刊
CiteScore
4.10
自引率
0.00%
发文量
193
审稿时长
66 days
期刊介绍: The European Journal of Medical Genetics (EJMG) is a peer-reviewed journal that publishes articles in English on various aspects of human and medical genetics and of the genetics of experimental models. Original clinical and experimental research articles, short clinical reports, review articles and letters to the editor are welcome on topics such as : • Dysmorphology and syndrome delineation • Molecular genetics and molecular cytogenetics of inherited disorders • Clinical applications of genomics and nextgen sequencing technologies • Syndromal cancer genetics • Behavioral genetics • Community genetics • Fetal pathology and prenatal diagnosis • Genetic counseling.
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