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Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human.

ABSTRACT: The human zona pellucida (ZP) is a highly organized glycoprotein matrix that encircles oocytes and plays an essential role in successful reproduction. Previous studies have reported that mutations in human ZP1, ZP2 and ZP3 influence their functions and result in a lack of ZP or in an abnormal oocytes and empty follicle syndrome, which leads to female infertility. Here, we performed whole-exome sequencing in two probands with primary infertility whose oocytes lacked a ZP, and we identified a heterozygous mutation in ZP1 (NM_207341:c.326G>A p.Arg109His), which is situated in the N-terminus, and a heterozygous mutation in ZP3 (NM_001110354:c.400G>A p.Ala134Thr), which is situated in the ZP domain. The effects of the mutations were investigated through structure prediction and in vitro studies in HeLa cells. The results, which were in line with the phenotype, suggested that these mutations might impede the function of cross-linking and secretion of ZP proteins. Our study showed that the two mutations in ZP1 and ZP3 influenced the formation of the ZP, causing female infertility. Meanwhile, these data highlight the importance of the ZP1 N-terminus in addition to the conserved domains for ZP1 function and ZP formation. Additionally, the patient with the ZP1 mutation delivered a baby following intracytoplasmic sperm injection (ICSI); thus, we suggest the targeted genetic diagnosis of ZP genes to choose appropriate fertilization methods and improve the success rate of assisted reproductive technology (ART) treatments.

SUBMITTER: Cao Q

PROVIDER: S-EPMC7412702 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human.

Cao Qiqi Q Zhao Chun C Zhang Xiaolan X Zhang Heng H Lu Qianneng Q Wang Congjing C Hu Yue Y Ling Xiufeng X Zhang Junqiang J Huo Ran R

Journal of cellular and molecular medicine 20200622 15

The human zona pellucida (ZP) is a highly organized glycoprotein matrix that encircles oocytes and plays an essential role in successful reproduction. Previous studies have reported that mutations in human ZP1, ZP2 and ZP3 influence their functions and result in a lack of ZP or in an abnormal oocytes and empty follicle syndrome, which leads to female infertility. Here, we performed whole-exome sequencing in two probands with primary infertility whose oocytes lacked a ZP, and we identified a hete ...[more]

PMID: 32573113

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Project description:To identify genetic mutations in three families with early onset high myopia (eoHM) limited to female members.Genomic DNA was collected from participating members of families XF1, XF2, and XF3. Genome-wide linkage scans were performed on the largest family (XF1). Whole exome sequencing was performed on seven samples, including five samples (four affected and one unaffected) from family XF1, as well as the two probands from family XF2 and XF3. Variants were analyzed with multistep bioinformatics analyses. Sanger-dideoxy sequencing was used to verify candidate variations in families and controls.The genome-wide linkage scans performed on family XF1 detected a candidate locus on chromosome Xp11.1-Xq13.3 with a maximum logarithm of the odds (LOD) score of 2.48 and 3.01 for markers DXS991 and DXS986, respectively. Parallel whole exome sequencing identified a novel c.893C>A (p.Ala298Asp) mutation in ARR3 located on Xq13.1 in family XF1, which was shared by all four affected individuals but not the unaffected individual. Two other novel mutations in ARR3, c.298C>T (p.Arg100*) and c.239T>C (p.Leu80Pro), were detected in families XF2 and XF3, respectively. These mutations were predicted to be damaging and were not present in the normal controls and existing databases. All three mutations cosegregated with eoHM in each of the three families, in which all heterozygous female members are affected whereas all hemizygous male family members are not affected. Transmission of the mutations and eoHM in the three families demonstrates an unusual pattern of X-linked female-limited inheritance.These data suggest that heterozygous mutations in ARR3 might be responsible for X-linked female-limited eoHM in the three families, a pattern contrary to the standard X-linked recessive trait. To our knowledge, eoHM is the first human disease associated with mutations in ARR3 and the second X-linked female-limited disease identified thus far. Identification of ARR3 associated with X-linked female-limited trait provides not only additional evidence of this unusual hereditary pattern but also an additional model for investigating the molecular mechanism responsible for female-limited phenotypes.

Dataset Information

Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human.

Publications

Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human.

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