Gene copy number reduction in the azoospermia factor c (AZFc) region and its effect on total motile sperm count

• Published in: Human molecular genetics 2011-06, Vol.20 (12), p.2457-2463
• Main Authors: NOORDAM, Michiel J, HENRIKE WESTERVELD, G, HOVINGH, Suzanne E, VAN DAALEN, Saskia K. M, KORVER, Cindy M, VAN DER VEEN, Fulco, VAN PELT, Ans M. M, REPPING, Sjoerd
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Gene Dosage - genetics; Gene Dosage - physiology; Genetic Loci; Genetics of eukaryotes. Biological and molecular evolution; Humans; Male; Molecular and cellular biology; Phenotype; Polymerase Chain Reaction; Seminal Plasma Proteins - genetics; Seminal Plasma Proteins - metabolism; Sperm Count; Sperm Motility - genetics; Statistics, Nonparametric; Testis - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr119

The azoospermia factor c (AZFc) region harbors multi-copy genes that are expressed in the testis. Deletions of the AZFc region lead to reduced copy numbers of these genes. Four (partial) AZFc deletions have been described of which the b2/b4 and gr/gr deletions affect semen quality. In most studies, (partial) AZFc deletions are identified and characterized using plus/minus sequence site tag (STS) polymerase chain reaction (PCR). However, secondary duplications increase the gene copy number without re-introducing the STS boundary marker. Consequently, the actual copy number of AZFc genes cannot be determined via STS PCR. In the current study, we first set out to determine by quantitative real-time PCR the actual copy number of all AZFc genes in men with (partial) AZFc deletions based on STS PCR. We then analyzed whether reduced gene copy numbers of each AZFc gene family were associated with reduced total motile sperm count (TMC), regardless of the type of deletion. We screened 840 men and identified 31 unrelated men with (partial) deletions of AZFc based on STS PCR. Of these 31 men, 6 men (19%) had one or more secondary duplications. For all AZFc genes, we found an association between a reduction in the copy number of each individual AZFc gene and reduced TMC. In gr/gr-deleted men, restoration of reduced gene copy numbers restored their TMC to normal values. Our findings suggest that the gene content of the AZFc region has been preserved throughout evolution through a dosage effect of the AZFc genes on TMC safeguarding male fertility.