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NovelCFAP43 andCFAP44 mutations cause male infertility with multiple morphological abnormalities of the sperm flagella (MMAF).
Reprod Biomed Online. 2019 May; 38(5):769-778.RB

Abstract

RESEARCH QUESTION

Multiple morphological abnormalities of the sperm flagella (MMAF) comprise a rare congenital disease that can cause primary male infertility. Several pathogenic genes (e.g. AKAP4, DNAH1, CFAP43 and CFAP44) are associated with MMAF but the pathogenic mechanisms have not been elucidated.

DESIGN

Whole-exome sequencing (WES) was applied to identify the pathogenic genes in 13 Chinese patients with MMAF; the patients were unrelated but all had consanguineous parents (usually first cousins). Real-time polymerase chain reaction and immunofluorescence staining were employed to assess the pathogenicity of these mutations.

RESULTS

Four novel homozygous CFAP43 mutations in four (30.8%) MMAF patients and one novel homozygous CFAP44 mutation in one (7.7%) other case were identified. The four novel homozygous CFAP43 mutations included one frameshift mutation (c.1140_1143del: p.Asn380Lysfs*3), one nonsense mutation (c.739A>T: p.Lys247*) and two missense mutations (c.1474G>C: p.Gln492Arg; c.4600C>G: p.Leu1534Val). The novel mutation in CFAP44 was a homozygous nonsense mutation (c.4963C>T: p.Arg1655*). Co-segregation of the mutations was verified by Sanger sequencing of the families. The relative mRNA expression levels of CFAP43 in patients 1 and 9 and the levels of CFAP44 in patient 5 were significantly lower than those in control sperm samples. Immunofluorescence analysis of CFAP43 showed the protein was absent in the sperm flagella of patients 1 and 9. Furthermore, two previously reported mutations of DNAH1 were also identified in another four (30.8%) patients.

CONCLUSIONS

This study demonstrated that CFAP43 and CFAP44 mutations are important causes of MMAF in the Chinese population. These novel mutations broaden the spectrum of CFAP43 and CFAP44 mutations.

Authors+Show Affiliations

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.Obstetrics and Gynecology Hospital, School of Life Sciences, Fudan University, Shanghai 200011, China; NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.Obstetrics and Gynecology Hospital, School of Life Sciences, Fudan University, Shanghai 200011, China; NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.Obstetrics and Gynecology Hospital, School of Life Sciences, Fudan University, Shanghai 200011, China; NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.Obstetrics and Gynecology Hospital, School of Life Sciences, Fudan University, Shanghai 200011, China; NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China. Electronic address: zhangfeng@fudan.edu.cn.Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China. Electronic address: caoyunxia6@126.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30904354

Citation

Wu, Huan, et al. "NovelCFAP43 andCFAP44 Mutations Cause Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella (MMAF)." Reproductive Biomedicine Online, vol. 38, no. 5, 2019, pp. 769-778.
Wu H, Li W, He X, et al. NovelCFAP43 andCFAP44 mutations cause male infertility with multiple morphological abnormalities of the sperm flagella (MMAF). Reprod Biomed Online. 2019;38(5):769-778.
Wu, H., Li, W., He, X., Liu, C., Fang, Y., Zhu, F., Jiang, H., Liu, W., Song, B., Wang, X., Zhou, P., Wei, Z., Zhang, F., & Cao, Y. (2019). NovelCFAP43 andCFAP44 mutations cause male infertility with multiple morphological abnormalities of the sperm flagella (MMAF). Reproductive Biomedicine Online, 38(5), 769-778. https://doi.org/10.1016/j.rbmo.2018.12.037
Wu H, et al. NovelCFAP43 andCFAP44 Mutations Cause Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella (MMAF). Reprod Biomed Online. 2019;38(5):769-778. PubMed PMID: 30904354.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NovelCFAP43 andCFAP44 mutations cause male infertility with multiple morphological abnormalities of the sperm flagella (MMAF). AU - Wu,Huan, AU - Li,Weiyu, AU - He,Xiaojin, AU - Liu,Chunyu, AU - Fang,Youyan, AU - Zhu,Fuxi, AU - Jiang,Huanhuan, AU - Liu,Wangjie, AU - Song,Bing, AU - Wang,Xue, AU - Zhou,Ping, AU - Wei,Zhaolian, AU - Zhang,Feng, AU - Cao,Yunxia, Y1 - 2018/12/23/ PY - 2018/05/11/received PY - 2018/10/05/revised PY - 2018/12/10/accepted PY - 2019/3/25/pubmed PY - 2020/4/28/medline PY - 2019/3/25/entrez KW - CFAP43 KW - CFAP44 KW - MMAF KW - Male infertility KW - Sperm flagella KW - WES SP - 769 EP - 778 JF - Reproductive biomedicine online JO - Reprod. Biomed. Online VL - 38 IS - 5 N2 - RESEARCH QUESTION: Multiple morphological abnormalities of the sperm flagella (MMAF) comprise a rare congenital disease that can cause primary male infertility. Several pathogenic genes (e.g. AKAP4, DNAH1, CFAP43 and CFAP44) are associated with MMAF but the pathogenic mechanisms have not been elucidated. DESIGN: Whole-exome sequencing (WES) was applied to identify the pathogenic genes in 13 Chinese patients with MMAF; the patients were unrelated but all had consanguineous parents (usually first cousins). Real-time polymerase chain reaction and immunofluorescence staining were employed to assess the pathogenicity of these mutations. RESULTS: Four novel homozygous CFAP43 mutations in four (30.8%) MMAF patients and one novel homozygous CFAP44 mutation in one (7.7%) other case were identified. The four novel homozygous CFAP43 mutations included one frameshift mutation (c.1140_1143del: p.Asn380Lysfs*3), one nonsense mutation (c.739A>T: p.Lys247*) and two missense mutations (c.1474G>C: p.Gln492Arg; c.4600C>G: p.Leu1534Val). The novel mutation in CFAP44 was a homozygous nonsense mutation (c.4963C>T: p.Arg1655*). Co-segregation of the mutations was verified by Sanger sequencing of the families. The relative mRNA expression levels of CFAP43 in patients 1 and 9 and the levels of CFAP44 in patient 5 were significantly lower than those in control sperm samples. Immunofluorescence analysis of CFAP43 showed the protein was absent in the sperm flagella of patients 1 and 9. Furthermore, two previously reported mutations of DNAH1 were also identified in another four (30.8%) patients. CONCLUSIONS: This study demonstrated that CFAP43 and CFAP44 mutations are important causes of MMAF in the Chinese population. These novel mutations broaden the spectrum of CFAP43 and CFAP44 mutations. SN - 1472-6491 UR - https://www.unboundmedicine.com/medline/citation/30904354/NovelCFAP43_andCFAP44_mutations_cause_male_infertility_with_multiple_morphological_abnormalities_of_the_sperm_flagella__MMAF__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1472-6483(18)30666-7 DB - PRIME DP - Unbound Medicine ER -