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

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


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


          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.


          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.


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

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          Most cited references 34

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          HomozygosityMapper—an interactive approach to homozygosity mapping

          Homozygosity mapping is a common method for mapping recessive traits in consanguineous families. In most studies, applications for multipoint linkage analyses are applied to determine the genomic region linked to the disease. Unfortunately, these are neither suited for very large families nor for the inclusion of tens of thousands of SNPs. Even if less than 10 000 markers are employed, such an analysis may easily last hours if not days. Here we present a web-based approach to homozygosity mapping. Our application stores marker data in a database into which users can directly upload their own SNP genotype files. Within a few minutes, the database analyses the data, detects homozygous stretches and provides an intuitive graphical interface to the results. The homozygosity in affected individuals is visualized genome-wide with the ability to zoom into single chromosomes and user-defined chromosomal regions. The software also displays the underlying genotypes in all samples. It is integrated with our candidate gene search engine, GeneDistiller, so that users can interactively determine the most promising gene. They can at any point restrict access to their data or make it public, allowing HomozygosityMapper to be used as a data repository for homozygosity-mapping studies. HomozygosityMapper is available at http://www.homozygositymapper.org/.
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            Mitochondria functionality and sperm quality.

            Although mitochondria are best known for being the eukaryotic cell powerhouses, these organelles participate in various cellular functions besides ATP production, such as calcium homoeostasis, generation of reactive oxygen species (ROS), the intrinsic apoptotic pathway and steroid hormone biosynthesis. The aim of this review was to discuss the putative roles of mitochondria in mammalian sperm function and how they may relate to sperm quality and fertilisation ability, particularly in humans. Although paternal mitochondria are degraded inside the zygote, sperm mitochondrial functionality seems to be critical for fertilisation. Indeed, changes in mitochondrial integrity/functionality, namely defects in mitochondrial ultrastructure or in the mitochondrial genome, transcriptome or proteome, as well as low mitochondrial membrane potential or altered oxygen consumption, have been correlated with loss of sperm function (particularly with decreased motility). Results from genetically engineered mouse models also confirmed this trend. On the other hand, increasing evidence suggests that mitochondria derived ATP is not crucial for sperm motility and that glycolysis may be the main ATP supplier for this particular aspect of sperm function. However, there are contradictory data in the literature regarding sperm bioenergetics. The relevance of sperm mitochondria may thus be associated with their role in other physiological features, particularly with the production of ROS, which in controlled levels are needed for proper sperm function. Sperm mitochondria may also serve as intracellular Ca²⁺ stores, although their role in signalling is still unclear.
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              Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella.

              Ten to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum.

                Author and article information

                J Med Genet
                J. Med. Genet
                Journal of Medical Genetics
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                November 2019
                14 August 2019
                : 56
                : 11
                : 750-757
                [1 ] departmentInstitute 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 ] departmentDepartment of Pathology, School of Basic Medical Science , Central South University , Changsha, China
                [5 ] National Engineering and Research Center of Human Stem Cell , Changsha, China
                Author notes
                [Correspondence to ] Dr Yue-Qiu Tan, Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; tanyueqiu@ 123456csu.edu.cn
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/.

                Funded by: Graduate Research and Innovation Projects of Central South University;
                Award ID: 2019zzts322
                Funded by: the National Key Research and Development Program of China;
                Award ID: 2016YFC1000206
                Funded by: the National Natural Science Foundation of China;
                Award ID: 81771645
                Funded by: the National Key Science Program S&T Program;
                Award ID: 2018YFC1004900
                Funded by: the science and technology major project of the ministry of science and technology of Hunan Province;
                Award ID: 2017SK1030
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