Spermatogenic Failure 19

A number sign (#) is used with this entry because of evidence that spermatogenic failure-19 (SPGF19) is caused by homozygous or compound heterozygous mutation in the CFAP43 gene (617558) on chromosome 10q25.

Description

Spermatogenic failure-19 is characterized by multiple morphologic abnormalities of the flagella (MMAF), including absent, short, coiled, bent, and irregular-caliber flagella (Tang et al., 2017).

For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Clinical Features

Tang et al. (2017) studied 3 Han Chinese men (P003, P028, and P029) with infertility due to multiple morphologic abnormalities of sperm flagella, who were compound heterozygous for mutations in the CFAP43 gene. All had severe to complete asthenospermia, and none of their spermatozoa showed progressive motility. Morphologic assessment by light microscopy showed severely distorted sperm flagella, including absent, short, coiled, bent, and irregular-caliber flagella. Spermatozoa with abnormal flagella represented approximately 80 to 100% of the spermatozoa analyzed, with short, coiled, and absent flagella being the most frequently observed. Transmission electron microscopy revealed disorganization of the fibrous sheaths and other axonemal and periaxonemal structures. Cross-sections showed hypertrophy and hyperplasia of the fibrous sheaths. Central microtubules were absent in most flagella, and various cytoskeletal components were distorted as well. The presence or absence of other features associated with primary ciliary dyskinesia (see 244400) was not reported.

Coutton et al. (2018) studied the ultrastructure of sperm cells from a Tunisian man (P43-8) with infertility due to MMAF and mutation in the CFAP43 gene. Longitudinal sections showed severe axonemal and periaxonemal defects affecting the outer dense fibers, the fibrous sheath, and the mitochondrial sheath, which appeared completely disorganized resulting in aborted flagella or their replacement by a cytoplasmic mass containing unassembled axonemal components. Approximately 95% of cross-sections were abnormal; the main defect was absence of the central pair complex (CPC; 9+0 conformation), observed in 81.8% of patient sperm compared to 0% in a fertile control. In the 5% of axonemes that had a normal 9+2 conformation, periaxonemal structure abnormalities were consistently observed. In addition, the absent-CPC defect was associated with peripheral doublet disorganization in 13.6% of sperm analyzed, and cross-sections with a single central microtubule (9+1 conformation) were observed in about 10% of cases. Immunofluorescence analysis using antibodies targeting the CPC protein SPAG6 (605730) showed no staining, and that of the radial spoke head protein RSPH1 (609314) was completely abnormal, with markedly diffuse staining concentrated in the midpiece.

Molecular Genetics

In 30 unrelated Han Chinese men with infertility due to multiple morphologic abnormalities of the flagella, Tang et al. (2017) performed whole-exome sequencing and aCGH assays and identified compound heterozygosity for mutations in the CFAP43 gene (617558.0001-617558.0005) in 3 patients. In addition, homozygosity for a mutation in the CFAP44 gene (617559.0001) was detected in 1 patient (see SPGF20, 617593), and 1 patient was homozygous for a nonsense mutation in the CFAP65 gene (614270). None of the mutations in CFAP43, CFAP44, or CFAP65 was found in 984 ethnically matched controls, and no homozygous loss-of-function mutations in these genes were reported in more than 100,000 individuals from the ExAC Browser or gnomAD databases.

By whole-exome sequencing in a cohort of 27 Chinese men with infertility due to MMAF, Sha et al. (2019) identified 1 patient who was homozygous for a splice site mutation in the CFAP43 gene (617558.0006). His unaffected father and mother were both heterozygous for the mutation, which was not found in the ExAC or 1000 Genomes databases.

By whole-exome sequencing in a cohort of 78 infertile men with MMAF, including 46 from North Africa, 10 from the Middle East, and 22 from France, who were negative for mutations in known male infertility-associated genes, Coutton et al. (2018) identified 10 patients who were homozygous or compound heterozygous for mutations in the CFAP43 gene (see, e.g., 617558.0007-617558.0011). The authors noted that 1 patient (P43-9) with a missense mutation on 1 allele (V347A; 617558.0011) exhibited a relatively milder phenotype, with 10% of spermatozoa that were morphologically normal and only 20% with short flagella, compared to 0% and a mean of approximately 65%, respectively, in the other CFAP43-mutated patients, who were all homozygous for truncating mutations.