Spermatogenic Failure 38

A number sign (#) is used with this entry because of evidence that spermatogenic failure-38 (SPGF38) is caused by homozygous mutation in the ARMC2 gene (618424) on chromosome 6q21.

For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Description

Spermatogenic failure-38 (SPGF38) is characterized by primary infertility and asthenoteratozoospermia due to multiple morphologic abnormalities of the flagella (MMAF). Spermatozoa show total sperm motility below 10% and exhibit morphologic anomalies including short, absent, coiled, bent, or irregular-caliber flagella (Coutton et al., 2019).

Clinical Features

Coutton et al. (2019) studied 5 infertile men with MMAF and severe asthenoteratozoospermia. Semen volumes were normal with low sperm concentrations, and total motility was 6% or less, with some patients showing no motile sperm. Three patients had no normal spermatozoa, and the other 2 patients showed 2% and 3% normal sperm, respectively. The most common flagellar abnormality was irregular-caliber flagella, followed by short, absent, coiled, and bent flagella. Abnormal sperm heads were observed, including tapered, thin, and microcephalic, as well as multiple heads. A high proportion of sperm in some patients also showed an abnormal acrosomal region and abnormal base. Transmission electron microscopy was performed in sperm cells from 1 patient (ARMC2_1), in whom the main defect observed was the absence of the central-pair complex (9 + 0 conformation). Some sections showed severe axonemal disorganization associated with periaxonemal structural defects such as unassembled outer dense fibers. Rare longitudinal sections showed severe abnormalities such as truncated flagella or the presence of cytoplasmic structures encompassing unassembled axonemal components. Immunofluorescence analysis of sperm from patient ARMC2_1 showed total absence of SPAG6 (605730), an axoneme central-pair complex protein.

Molecular Genetics

In a cohort of 167 infertile men with MMAF, Coutton et al. (2019) performed whole-exome sequencing and identified 4 men with homozygous variants in the ARMC2 gene, including a splicing mutation (618424.0001), a missense mutation (I760N; 618424.0002), a 2-bp deletion (618424.0003), and a 5-bp deletion (618424.0004). In addition, a Chinese man with primary infertility and typical MMAF was found to be homozygous for an ARMC2 nonsense mutation (Q141X; 618424.0005), which segregated with disease in his family. All 5 men were negative for pathologic mutations in other MMAF-associated genes, and none of the ARMC2 mutations were found in in-house controls or in public variant databases.