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  • BMJ  (3)
  • 1
    Online Resource
    Online Resource
    Homozygous mutations in DZIP1 can induce asthenoteratospermia with severe MMAF
    BMJ ; 2020
    In:  Journal of Medical Genetics Vol. 57, No. 7 ( 2020-07), p. 445-453
    Details
    In: Journal of Medical Genetics, BMJ, Vol. 57, No. 7 ( 2020-07), p. 445-453
    Abstract: Asthenoteratospermia, one of the most common causes for male infertility, often presents with defective sperm heads and/or flagella. Multiple morphological abnormalities of the sperm flagella (MMAF) is one of the common clinical manifestations of asthenoteratospermia. Variants in several genes including DNAH1 , CEP135 , CATSPER2 and SUN5 are involved in the genetic pathogenesis of asthenoteratospermia. However, more than half of the asthenoteratospermia cases cannot be explained by the known pathogenic genes. Methods and results Two asthenoteratospermia-affected men with severe MMAF (absent flagella in 〉 90% spermatozoa) from consanguineous families were subjected to whole-exome sequencing. The first proband had a homozygous missense mutation c.188G 〉 A (p.Arg63Gln) of DZIP1 and the second proband had a homozygous stop-gain mutation c.690T 〉 G (p.Tyr230*). Both of the mutations were neither detected in the human population genome data (1000 Genomes Project, Exome Aggregation Consortium) nor in our own data of a cohort of 875 Han Chinese control populations. DZIP1 encodes a DAZ (a protein deleted in azoospermia) interacting protein, which was associated with centrosomes in mammalian cells. Immunofluorescence staining of the centriolar protein Centrin1 indicated that the spermatozoa of the proband presented with abnormal centrosomes, including no concentrated centriolar dot or more than two centriolar dots. HEK293T cells transfected with two DZIP1 -mutated constructs showed reduced DZIP1 level or truncated DZIP1. The Dzip1 -knockout mice, generated by the CRSIPR-Cas9, revealed consistent phenotypes of severe MMAF. Conclusion Our study strongly suggests that homozygous DZIP1 mutations can induce asthenoteratospermia with severe MMAF. The deficiency of DZIP1 induces sperm centrioles dysfunction and causes the absence of flagella.
    Type of Medium: Online Resource
    ISSN: 0022-2593 , 1468-6244
    URL: Article
    DOI: 10.1136/jmedgenet-2019-106479
    RVK:
    WA 15000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2009590-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 2
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    Online Resource
    Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella
    BMJ ; 2019
    In:  Journal of Medical Genetics Vol. 56, No. 2 ( 2019-02), p. 96-103
    Details
    In: Journal of Medical Genetics, BMJ, Vol. 56, No. 2 ( 2019-02), p. 96-103
    Abstract: Male infertility is a major issue of human reproduction health. Asthenoteratospermia can impair sperm motility and cause male infertility. Asthenoteratospermia with multiple morphological abnormalities of the flagella (MMAF) presents abnormal spermatozoa with absent, bent, coiled, short and/or irregular-calibre flagella. Previous studies on MMAF reported that genetic defects in cilia-related genes (eg, AKAP4 , DNAH1 , CFAP43 , CFAP44 and CFAP69 ) are the major cause of MMAF. However, the known MMAF-associated genes are only responsible for approximately 30% to 50% of human cases. We further investigated the cases with MMAF in search of additional genes mutated in this condition. Methods and results We conducted whole exome sequencing in a male individual with MMAF from a consanguineous Han Chinese family. Sanger sequencing was also conducted in additional individuals with MMAF. Intriguingly, a homozygous frameshift mutation (p.Leu357Hisfs*11) was identified in the gene encoding CFAP69 (cilia and flagella-associated protein 69), which is highly expressed in testis. The subsequent Sanger sequencing of the CFAP69 coding regions among 34 additional individuals with MMAF revealed a case with homozygous nonsense mutation (p.Trp216*) of CFAP69 . Both of these CFAP69 loss-of-function mutations were not present in the human population genome data archived in the 1000 Genomes Project and ExAC databases, nor in 875 individuals of two Han Chinese control populations. Furthermore, we generated the knockout model in mouse orthologue Cfap69 using the CRISPR-Cas9 technology. Remarkably, male Cfap69 -knockout mice manifested with MMAF phenotypes. Conclusion Our experimental findings elucidate that homozygous loss-of-function mutations in CFAP69 can lead to asthenoteratospermia with MMAF in humans and mice.
    Type of Medium: Online Resource
    ISSN: 0022-2593 , 1468-6244
    URL: Article
    URL: Article
    DOI: 10.1136/jmedgenet-2018-105486
    DOI: 10.1136/jmedgenet-2018-105486.supp1
    RVK:
    WA 15000
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 2009590-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility
    BMJ ; 2020
    In:  Journal of Medical Genetics Vol. 57, No. 1 ( 2020-01), p. 31-37
    Details
    In: Journal of Medical Genetics, BMJ, Vol. 57, No. 1 ( 2020-01), p. 31-37
    Abstract: Male infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) is a genetically heterogeneous disorder. Previous studies revealed several MMAF-associated genes, which account for approximately 60% of human MMAF cases. The pathogenic mechanisms of MMAF remain to be illuminated. Methods and results We conducted genetic analyses using whole-exome sequencing in 50 Han Chinese probands with MMAF. Two homozygous stop-gain variants (c.910C 〉 T (p.Arg304*) and c.3400delA (p.Ile1134Serfs*13)) of the SPEF2 ( sperm flagellar 2 ) gene were identified in two unrelated consanguineous families. Consistently, an Iranian subject from another cohort also carried a homozygous SPEF2 stop-gain variant (c.3240delT (p.Phe1080Leufs*2)). All these variants affected the long SPEF2 transcripts that are expressed in the testis and encode the IFT20 (intraflagellar transport 20) binding domain, important for sperm tail development. Notably, previous animal studies reported spontaneous mutations of SPEF2 causing sperm tail defects in bulls and pigs. Our further functional studies using immunofluorescence assays showed the absence or a remarkably reduced staining of SPEF2 and of the MMAF-associated CFAP69 protein in the spermatozoa from SPEF2 -affected subjects. Conclusions We identified SPEF2 as a novel gene for human MMAF across the populations. Functional analyses suggested that the deficiency of SPEF2 in the mutated subjects could alter the localisation of other axonemal proteins.
    Type of Medium: Online Resource
    ISSN: 0022-2593 , 1468-6244
    URL: Article
    DOI: 10.1136/jmedgenet-2019-106011
    RVK:
    WA 15000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2009590-9
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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