Novel biallelic loss-of-function mutations in CFAP43 cause multiple morphological abnormalities of the sperm flagellum in Pakistani families.
Novel biallelic loss-of-function mutations in CFAP43 cause multiple morphological abnormalities of the sperm flagellum in Pakistani families.
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CFAP43 中新型双等位基因功能丧失突变导致巴基斯坦家庭精子鞭毛的多种形态异常。
DOI：
10.4103/aja.aja_26_21
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发表时间：
2021-11
影响因子：
2.9
通讯作者：
Shi QH
中科院分区：
文献类型：
--
作者：
Khan I;Shah B;Dil S;Ullah N;Zhou JT;Zhao DR;Zhang YW;Jiang XH;Khan R;Khan A;Ali H;Zubair M;Shah W;Zhang H;Shi QH
精子鞭毛多形态异常（Multiple morphological abnormalities of the sperm flagella，MMAF）是弱畸形精子症的一种特殊类型，表现为精子鞭毛缺失、弯曲、卷曲、短或不规则等多种形态异常。先前的遗传研究揭示了编码纤毛和鞭毛相关蛋白（CFAP;例如，CFAP 43、CFAP 44、CFAP 65、CFAP 69、CFAP 70和CFAP 251）负责来自不同种族群体的不育男性中的MMAF表型。然而，在患有MMAF的不育巴基斯坦男性中没有发现任何一种。在目前的研究中，招募了两个患有MMAF患者的巴基斯坦家庭。对患者及其父母进行全外显子组测序（WES）。WES分析反映了两个家族中CFAP 43的新型双等位基因功能丧失突变（家族1：ENST 00000357060.3，p.Arg300Lysfs*22和p.Thr526Serfs*43处于复合杂合状态;家族2：ENST 00000357060.3，p.Thr526Serfs*43处于纯合状态）。桑格测序进一步证实，这些突变在具有MMAF表型的家族中是分离的。半定量逆转录聚合酶链反应（qRT-PCR）检测突变对相关基因mRNA的影响。先前的研究表明，CFAP 43中的双等位基因功能丧失突变占所有CFAP 43突变型MMAF患者的大多数。据我们所知，这是第一个研究报告CFAP 43双等位基因功能丧失突变的巴基斯坦人口与MMAF表型。本研究将有助于研究人员和临床医生更好地了解MMAF的遗传病因。
Multiple morphological abnormalities of the sperm flagella (MMAF) is a specific type of asthenoteratozoospermia, presenting with multiple morphological anomalies in spermatozoa, such as absent, bent, coiled, short, or irregular caliber flagella. Previous genetic studies revealed pathogenic mutations in genes encoding cilia and flagella-associated proteins (CFAPs; e.g., CFAP43, CFAP44, CFAP65, CFAP69, CFAP70, and CFAP251) responsible for the MMAF phenotype in infertile men from different ethnic groups. However, none of them have been identified in infertile Pakistani males with MMAF. In the current study, two Pakistani families with MMAF patients were recruited. Whole-exome sequencing (WES) of patients and their parents was performed. WES analysis reflected novel biallelic loss-of-function mutations in CFAP43 in both families (Family 1: ENST00000357060.3, p.Arg300Lysfs*22 and p.Thr526Serfs*43 in a compound heterozygous state; Family 2: ENST00000357060.3, p.Thr526Serfs*43 in a homozygous state). Sanger sequencing further confirmed that these mutations were segregated recessively in the families with the MMAF phenotype. Semiquantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was carried out to detect the effect of the mutation on mRNA of the affected gene. Previous research demonstrated that biallelic loss-of-function mutations in CFAP43 accounted for the majority of all CFAP43-mutant MMAF patients. To the best of our knowledge, this is the first study to report CFAP43 biallelic loss-of-function mutations in a Pakistani population with the MMAF phenotype. This study will help researchers and clinicians to understand the genetic etiology of MMAF better.
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