Novel missense mutations of the Deleted-in-AZoospermia-Like (DAZL) gene in infertile women and men

Here we sought to identify rare mutations in DAZL and examine their phenotypes in men and women. We sequenced the DAZL gene in 519 individuals; sequences spanned the entire coding region of the gene.We report the identification of four putative missense mutations in DAZL. Three individuals that were heterozygous for a DAZL mutation reported having children, while two individuals that were homozygous reported no children. These mutations were found only in infertile men and women.Given the strong data associating DAZL polymorphisms and deletions with fertility in humans and model organisms, we suggest that these mutations may be associated with age at menopause and/or sperm count and warrant further biochemical and genetic investigation.Though infertility affects 10–15% of couples, only a small number of genes have been shown to be associated with infertility in women and men [1]. In women, family history is a significant predictor of early menopause (menopause at age < 47 years); a woman with an immediate family member who experienced an early menopause has a 6-fold greater risk of early menopause herself [2,3]. In addition, sibling studies have estimated the heritability of age at onset of menopause to be high, 63% in one study and 85% in another [4,5]. In men, there are fewer studies that have examined the genetics of sperm production; most have focused on the role of the Y chromosome [6-8]. Indeed, the most common genetic lesion appears to be deletions of the Y chromosome, including deletions of the DAZ (Deleted-in-AZoospermia) gene, which are associated with azoospermia (no sperm in the ejaculate) and oligozoospermia (< 20 million sperm/mL of ejaculate) [6-8].As many features of germ cell development are similar in both sexes, we expect that some genes may function similarly in men and women. In humans and other mammals, male and female germ cells initially develop along the same path, but take different courses after the mitotic expansion of premeiotic germ cel