Gene deletions in an infertile man with sperm fibrous sheath dysplasia

Baccetti, Baccio; Collodel, Giulia; Estenoz, M; Manca, D.; Moretti, Elena; Piomboni, Paola

doi:10.1093/humrep/dei126

Cited by 123 publications

(94 citation statements)

References 20 publications

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“…2,3,15,16 However, the biallelic DNAH1 mutations identified in previous studies only accounted for 28%-44% of MMAF. 3,17,18 These observations suggested the existence of unknown genes associated with MMAF.…”

Section: Discussionmentioning

confidence: 88%

“…2,[10][11][12][13][14] So far, mutations in only three genes, AKAP4 (MIM: 300185), CCDC39 (MIM: 613798), and DNAH1 (MIM: 603332), have been formally identified to cause MMAF in humans. 2,3,15,16 Among them, biallelic DNAH1 mutations in MMAF have been recurrently identified across studies and account for 28%-44% of MMAF cases. 3,17,18 However, the genetic causes or molecular mechanisms in the other half of MMAF cases are still unclear, indicating the genetic heterogeneity of MMAF.…”

Section: Introductionmentioning

confidence: 99%

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Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Tang¹,

Wang

Li³

et al. 2017

The American Journal of Human Genetics

254

212

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Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAFassociated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia-and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43-and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Tang¹,

Wang

Li³

et al. 2017

The American Journal of Human Genetics

254

212

View full text Add to dashboard Cite

show abstract

“…However, consistent human data were reported from only one study. Baccetti et al [90] used PCR and observed intragenic deletions of AKAP4 and AKAP3, which code for major structural components of the fibrous sheath, in one DFS patient. No abnormality was detected in other samples.…”

Section: Dysplasia Of the Fibrous Sheath Of The Tailmentioning

confidence: 99%

Ultrastructure of Spermatozoa from Infertility Patients

Брагина¹,

Bocharova²

2018

Spermatozoa - Facts and Perspectives

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Standard examination of human semen currently remains a main test for examination of male fertility disorders. Although parameters of sperm quality in fertile men are generally higher than in sterile ones, there is a substantial overlap between the two populations, indicating that other important factors affect fertility, but are not assessed in conventional assay. Currently, tests determining the functional properties of sperm have been intensively developed. This review considers an electron microscopic examination of sperm, which assesses the structure and function of the sperm nuclear, penetration and motor apparatus. The detection of sperm chromatin structure can help to understand the causes of early embryonic malformation. Genetically caused and functional disorders of the structure and function of spermatozoa are discussed. Indications for electron microscopic examination of spermatozoa in fertility disorders are given.

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“…It was demonstrated that the absence of these proteins is associated to sperm immotility [10,8,11]. Baccetti et al, [11] have reported in one DFS patient a deletion of the AKAP4/AKAP3 binding regions and have suggested that in some cases the DFS sperm defect could be associated with alterations of AKAP3 and AKAP4 gene sequences.…”

Section: Introductionmentioning

confidence: 99%

“…Several proteins have been identified on isolated human sperm fibrous sheath [6,7], and only two proteins AKAP3 and AKAP4 (members of the A-kinase anchor protein family) involved in organizing the basic structure of the fibrous sheath [8] were described as the most abundant structural protein of the fibrous sheath [9]. It was demonstrated that the absence of these proteins is associated to sperm immotility [10,8,11]. Baccetti et al, [11] have reported in one DFS patient a deletion of the AKAP4/AKAP3 binding regions and have suggested that in some cases the DFS sperm defect could be associated with alterations of AKAP3 and AKAP4 gene sequences.…”

Section: Introductionmentioning

confidence: 99%

Meiotic segregation and sperm DNA fragmentation in Tunisian men with dysplasia of the fibrous sheath (DFS) associated with head abnormalities

Ghédir

Mehri

Mogharrabi

et al. 2014

J Assist Reprod Genet

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Purpose Dysplasia of the Fibrous Sheath (DFS) is a primitive flagellar pathology for which a broad spectrum of ultrastructural flagellar abnormalities has been described responsible for a severe to total asthenozoospermia. To this phenotype other morphological abnormalities including cephalic and abnormalities in nuclear structure can be associated that could compromise embryonic development in case of use of Assisted Reproductive Technology (ART). The aim of this study was to evaluate the level of DNA fragmentation and aneuploidy rate in ejaculated spermatozoa of Tunisian men presented with DFS sperm defect associated to high percentage of head abnormalities and to compare the results with those from fertile men. Methods Sperm DNA fragmentation was evaluated by the terminal desoxynucleotidyl transferase mediated deoxyuridine triphosphate biotin nick-end labelling (TUNEL) assay. The study of meiotic segregation was performed by Fluorescence in situ hybridization (FISH) for chromosomes X, Y and 18. Results The mean DNA fragmentation index was significantly higher in patients compared to the control group. FISH revealed a significantly higher incidence of sperm aneuploidies compared with controls. All patients showed elevated frequencies of sex chromosomes disomy, disomy 18 and diploidy. Conclusions In some cases of syndromic teratozoospermia due to sperm tail structural abnormalities, such as DFS, other morphological cephalic abnormalities may be associated. In these cases we have demonstrated impaired sperm nuclear quality which will affect the results in ICSI. Hence the interest of a thorough study of the sperm nucleus in these forms of infertility in order to predict the chances of success in ART.

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Gene deletions in an infertile man with sperm fibrous sheath dysplasia

Cited by 123 publications

References 20 publications

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Ultrastructure of Spermatozoa from Infertility Patients

Meiotic segregation and sperm DNA fragmentation in Tunisian men with dysplasia of the fibrous sheath (DFS) associated with head abnormalities

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