Mutation analysis of the MSH4 gene in men with maturation arrest of spermatogenesis

Introduction: Msh4 (MutS homolog 4) is a member of the mammalian mismatch repair gene family and involved in meiotic recombination. Mouse studies showed that Msh4-/- mice were infertile and that Msh4 is necessary for chromosome synapsis during early meiosis. To investigate the possibility that MSH4 is also involved in human spermatogenesis, we analyzed the DNA of patients with a maturation arrest of spermatogenesis for the presence of mutations in the MSH4 gene.
Patients and methods: Mutations were analyzed in the DNA of 40 patients with a maturation arrest of spermatogenesis. Patients were further subdivided according to their origin (Arabic vs Caucasian). Appropriate control groups consisted of men with normozoospermia.
Results: Four single nucleotide changes of the MSH4 gene altering the amino acid sequence were detected in the patient groups. All observed alterations were also present in our control groups with no significantly different frequencies.
Two alterations (c.289G>A and c.2520G>C) were present in patients from Arabic and Caucasian origin; while one alteration (c.1766A>G) was detected only in Caucasian patients and controls and the other (c.2741G>A) only in Arabic men.
Three of these alterations were already described in Genbank for Caucasian men (HapMAP-CEU). The change c.1766A>G was significantly more frequent in this population compared to our patients and controls, although our patient and control groups did not differ.
Discussion: All observed alterations in MSH4 were present in infertile patients and normozoospermic controls, indicating that the observed changes are not causing maturation arrest of spermatogenesis.