#619144
Table of Contents
A number sign (#) is used with this entry because of evidence that spermatogenic failure-49 (SPGF49) is caused by homozygous or compound heterozygous mutation in the CFAP58 gene (619129) on chromosome 10q25.
Spermatogenic failure-49 (SPGF49) is characterized by male infertility due to multiple morphologic abnormalities of the sperm flagella (MMAF), primarily coiled and short flagella, with markedly reduced or no progressive motility (He et al., 2020).
For a discussion of genetic heterogeneity of spermatogenic failure, see 258150.
He et al. (2020) reported 5 unrelated Chinese men (A050, A064, N010, N011, and N015) with infertility due to asthenoteratozoospermia. Sperm concentrations were normal or only slightly decreased, but there was no progressive motility in 4 of the 5 patients, and the fifth (N011) had a progressive motility rate of only 2.1%. Morphologic analysis showed that more than 94% of patient spermatozoa exhibited typical MMAF anomalies, primarily coiled and short flagella, but also absent, angulated, and irregular-caliber flagella. Transmission electron microscopy, undertaken in 3 patients (A050, A064, and N015), revealed that more than 90% of axonemal cross-sections had abnormalities, with most showing absence of the central pair (9+0 or 9+1 configuration) and/or absence of the microtubule doublets. The remainder showed complicated disorganization of the 9+2 structure, involving the central pair, microtubule doublets, nexin, dynein arms, mitochondrial sheath, and/or the outer dense fibers (ODFs). In 2 of the patients (A050 and A064) the number of ODFs was almost doubled in some of the flagellar midpieces. Immunofluorescence assay in A050, A064, and N015 demonstrated marked reduction or absence of SPAG6 (605730), a marker of the central pair, and SPEF2 (610172), a protein required for assembly of the flagella; these findings were confirmed by immunoblotting. Longitudinal sections of the flagella revealed further malformations, including a completely disorganized midpiece with misshapen mitochondrial sheath, fibrous sheath, and ODFs in patient A050, and abnormal flagellar assembly with a shortened mitochondrial sheath in patient N015. Immunofluorescence and immunoblotting assays for HSP60 (118190), a mitochondrial chaperonin, showed significantly decreased levels or absence of HSP60 in sperm cells from A050, A064, and N015.
The transmission pattern of SPGF49 in the families studied by He et al. (2020) was consistent with autosomal recessive inheritance.
In a cohort of 90 Chinese men with infertility due to MMAF, He et al. (2020) performed whole-exome sequencing and identified 5 unrelated probands with homozygosity or compound heterozygosity for frameshift or nonsense mutations in the CFAP58 gene (619129.0001-619129.0005). The unaffected parents were heterozygous for the respective mutation, which were absent or present at very low minor allele frequency in public variant databases.
He, X., Liu, C., Yang, X., Lv, M., Ni, X., Li, Q., Cheng, H., Liu, W., Tian, S., Wu, H., Gao, Y., Yang, C., and 20 others. Bi-allelic loss-of-function variants in CFAP58 cause flagellar axoneme and mitochondrial sheath defects and asthenoteratozoospermia in humans and mice. Am. J. Hum. Genet. 107: 514-526, 2020. [PubMed: 32791035, images, related citations] [Full Text]
ORPHA: 399808; DO: 0112271;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q25.1 | Spermatogenic failure 49 | 619144 | Autosomal recessive | 3 | CFAP58 | 619129 |
A number sign (#) is used with this entry because of evidence that spermatogenic failure-49 (SPGF49) is caused by homozygous or compound heterozygous mutation in the CFAP58 gene (619129) on chromosome 10q25.
Spermatogenic failure-49 (SPGF49) is characterized by male infertility due to multiple morphologic abnormalities of the sperm flagella (MMAF), primarily coiled and short flagella, with markedly reduced or no progressive motility (He et al., 2020).
For a discussion of genetic heterogeneity of spermatogenic failure, see 258150.
He et al. (2020) reported 5 unrelated Chinese men (A050, A064, N010, N011, and N015) with infertility due to asthenoteratozoospermia. Sperm concentrations were normal or only slightly decreased, but there was no progressive motility in 4 of the 5 patients, and the fifth (N011) had a progressive motility rate of only 2.1%. Morphologic analysis showed that more than 94% of patient spermatozoa exhibited typical MMAF anomalies, primarily coiled and short flagella, but also absent, angulated, and irregular-caliber flagella. Transmission electron microscopy, undertaken in 3 patients (A050, A064, and N015), revealed that more than 90% of axonemal cross-sections had abnormalities, with most showing absence of the central pair (9+0 or 9+1 configuration) and/or absence of the microtubule doublets. The remainder showed complicated disorganization of the 9+2 structure, involving the central pair, microtubule doublets, nexin, dynein arms, mitochondrial sheath, and/or the outer dense fibers (ODFs). In 2 of the patients (A050 and A064) the number of ODFs was almost doubled in some of the flagellar midpieces. Immunofluorescence assay in A050, A064, and N015 demonstrated marked reduction or absence of SPAG6 (605730), a marker of the central pair, and SPEF2 (610172), a protein required for assembly of the flagella; these findings were confirmed by immunoblotting. Longitudinal sections of the flagella revealed further malformations, including a completely disorganized midpiece with misshapen mitochondrial sheath, fibrous sheath, and ODFs in patient A050, and abnormal flagellar assembly with a shortened mitochondrial sheath in patient N015. Immunofluorescence and immunoblotting assays for HSP60 (118190), a mitochondrial chaperonin, showed significantly decreased levels or absence of HSP60 in sperm cells from A050, A064, and N015.
The transmission pattern of SPGF49 in the families studied by He et al. (2020) was consistent with autosomal recessive inheritance.
In a cohort of 90 Chinese men with infertility due to MMAF, He et al. (2020) performed whole-exome sequencing and identified 5 unrelated probands with homozygosity or compound heterozygosity for frameshift or nonsense mutations in the CFAP58 gene (619129.0001-619129.0005). The unaffected parents were heterozygous for the respective mutation, which were absent or present at very low minor allele frequency in public variant databases.
He, X., Liu, C., Yang, X., Lv, M., Ni, X., Li, Q., Cheng, H., Liu, W., Tian, S., Wu, H., Gao, Y., Yang, C., and 20 others. Bi-allelic loss-of-function variants in CFAP58 cause flagellar axoneme and mitochondrial sheath defects and asthenoteratozoospermia in humans and mice. Am. J. Hum. Genet. 107: 514-526, 2020. [PubMed: 32791035] [Full Text: https://doi.org/10.1016/j.ajhg.2020.07.010]
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