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J Med Genet. 2019 Aug 14. pii: jmedgenet-2019-106031. doi: 10.1136/jmedgenet-2019-106031. [Epub ahead of print]

Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations.

Wang W1, Tu C1,2, Nie H1,2, Meng L2, Li Y1, Yuan S2, Zhang Q1,3, Du J1,2, Wang J4, Gong F1,2, Fan L1,2, Lu GX2,5, Lin G1,2, Tan YQ6,2.

Author information

1
Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China.
2
Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.
3
NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Changsha, China.
4
Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China.
5
National Engineering and Research Center of Human Stem Cell, Changsha, China.
6
Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China tanyueqiu@csu.edu.cn.

Abstract

BACKGROUND:

The genetic causes for most male infertility due to severe asthenozoospermia remain unclear.

OBJECTIVE:

Our objective was to identify unknown genetic factors in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families.

METHODS:

We performed whole exome sequencing of 47 individuals with severe asthenozoospermia from 45 unrelated families. Mutation screening was performed in a control cohort of 637 individuals, including 219 with oligoasthenospermia, 195 with non-obstructive azoospermia and 223 fertile controls. Ultrastructural and immunostaining analyses of patients' spermatozoa were performed to characterise the effect of variants.

RESULTS:

One homozygous non-sense mutation (NM_194302, c.G5341T:p.E1781X), two compound heterozygous mutations (c.C2284T:p.R762X and c.1751delC:p.P584fs) and two compound heterozygous mutations (c.5714_5721del:p.L1905fs and c.C3021A:p.N1007K) were identified in CFAP65 of three individuals with completely immotile spermatozoa, respectively. No biallelic deleterious variants of CFAP65 were detected in the control cohort of 637 individuals. Ultrastructural and immunostaining analyses of spermatozoa from two patients showed highly aberrant sperm morphology with severe defects such as acrosome hypoplasia, disruption of the mitochondrial sheath and absence of the central pair complex.

CONCLUSION:

To the best of our knowledge, we are the first to report that CFAP65 mutations may cause spermatozoa to be completely immotile.

KEYWORDS:

CFAP65 mutation; acrosome; completely immotile spermatozoa; flagellum assembly; male infertility

PMID:
31413122
DOI:
10.1136/jmedgenet-2019-106031
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Conflict of interest statement

Competing interests: None declared.

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