Spermatogenic Failure 31

A number sign (#) is used with this entry because of evidence that spermatogenic failure-31 (SPGF31) is caused by homozygous or compound heterozygous mutation in the PMFBP1 gene (618085) on chromosome 16q22.

Description

SPGF31 is characterized by male infertility due to oligozoospermia with a high proportion (greater than 90%) of acephalic sperm. Affected couples may overcome infertility with intracytoplasmic sperm injection (Zhu et al., 2018).

For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see 258150.

Clinical Features

Zhu et al. (2018) studied 5 infertile 46,XY men from 4 unrelated families, 3 of whom had previously been studied by Zhu et al. (2016) and all of whom were negative for Y-chromosome microdeletions. All of the men were oligozoospermic, and semen analysis showed more than 95% acephalic spermatozoa in all of them. None of the men had any progressively motile spermatozoa, and most spermatozoa (70-95%) were immotile. No morphologically normal spermatozoa were observed: of sperm that were not acephalic, 1.6 to 4.3% showed an abnormal head-tail junction, and 0.1 to 0.8% were tailless. Three couples underwent intracytoplasmic sperm injection of head-tail sperm and all 3 became pregnant: 2 had healthy boys, and 1 was pregnant with twins who appeared normal at 18-week ultrasound.

Sha et al. (2019) reported 2 unrelated infertile 46,XY Chinese men. Proband P10, aged 33 years, had low sperm concentration, 18% sperm motility, 91% acephalic spermatozoa, 8% spermatozoa with round or amorphous heads, and 1% spermatozoa with normal morphology. The findings in proband P16, aged 31 years, were similar.

Molecular Genetics

In 2 infertile brothers with oligozoospermia and acephalic spermatozoa from a consanguineous Chinese family, Zhu et al. (2018) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the PMFBP1 gene (Q488X; 618085.0001). Analysis of 10 additional infertile Chinese men with acephalic spermatozoa, previously studied by Zhu et al. (2018) and known to be negative for mutation in the SUN5 gene (613942), revealed 3 unrelated men with homozygous or compound heterozygous mutations in PMFBP1 (see, e.g., 618085.0002 and 618085.0003). The mutations segregated with the phenotype in the 3 families for which parental DNA was available and were not found in 100 unrelated Chinese men or in the 1000 Genomes Project database.

In 2 infertile Chinese men (P10 and P16) with acephalic spermatozoa, Sha et al. (2019) identified homozygous or compound heterozygous mutations in the PMFBP1 gene (618085.0004-618085.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the 1000 Genomes Project database and were present at low frequencies in the ExAC database.