ABSTRACT
R-spondin proteins are secreted agonists of canonical WNT/ß-catenin signaling. Homozygous RSPO1 mutations cause a syndrome of 46,XX disorder of sexual development (DSD), palmoplantar keratoderma (PPK), and predisposition to squamous cell carcinoma. We report exome sequencing data of two 46,XX siblings, one with testicular DSD and the other with suspected ovotesticular DSD. Both have PPK and hearing impairment and carried a novel homozygous mutation c.332G>A (p.Cys111Tyr) located in the highly conserved furin-like cysteine-rich domain-2 (FU-CRD2). Cysteines in the FU-CRDs are strictly conserved, indicating their functional importance in WNT signaling through interaction with the leucine-rich repeat-containing G-protein-coupled receptors. This is the first RSPO1 missense mutation reported in association with human disease.
Subject(s)
46, XX Disorders of Sex Development/genetics , Thrombospondins/genetics , Adolescent , Adult , Amino Acid Sequence , Child , Female , Hearing Loss/genetics , Homozygote , Humans , Keratoderma, Palmoplantar/genetics , Male , Molecular Sequence Data , Mutation, Missense/genetics , Pedigree , Protein Domains/genetics , Protein Domains/physiology , Wnt Signaling Pathway/genetics , Wnt Signaling Pathway/physiology , Young AdultABSTRACT
BACKGROUND: Male infertility is responsible for 50% of infertile couples. Thirty percent of male infertility is due to cytogenetic and genetic abnormalities. In Arab and North African populations, several studies have shown the association of these chromosomal abnormalities with male infertility. Our objective is to evaluate the frequency of chromosomal abnormalities and Y chromosome microdeletions in infertile men from Morocco. METHODS: A total of 573 Moroccan infertile men (444 azoospermic and 129 oligozoospermic men) referred for cytogenetic analysis to the Department of Cytogenetics of the Pasteur Institute of Morocco, were screened for the presence of chromosomal abnormalities and Y chromosome microdeletions. RESULTS: Chromosomal abnormalities accounted for approximately 10.5% (60/573). Fifty six cases among them have sex chromosome abnormalities (93.34%), including Klinefelter's syndrome in 41 patients (68.34%). Autosomal chromosome abnormalities (6.66%) were observed in 4 patients. Chromosomal abnormalities were more prevalent in azoospermic men (13.06%) than in oligospermic men (1.55%). Y microdeletions were detected in 16 of 85 patients (AZFc: 14.12%, AZFbc: 4.70%), most of them where azoospermic men with no chromosomal abnormality. CONCLUSIONS: These results highlighted the need for efficient molecular genetic testing in male infertility diagnosis. In addition, a genetic screening should be performed in infertile men before starting assisted reproductive treatments.
