The X-linked human gene RBBP7 has been shown to play a key role in spermatogenesis; its deficiency has been postulated to lead to inherited predisposition to non-obstructive azoospermia and to the potential development of testicular tumors. There is a single fly ortholog, Caf1-55, for which multiple genetic reagents have been generated, including loss-of-function alleles, RNAi-targeting constructs, alleles caused by insertional mutagenesis, overexpression constructs, and a CRISPR/Cas9-based LOF construct.
Initially identified in a large-scale analysis of X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent and geographically separate cohorts, RBBP7 was found to be mutated in ten men across all cohorts. A subsequent study identified a variant of RBBP7 in two brothers with non-obstructive azoospermia; one brother also had a small testicular tumor.
UAS constructs of the human Hsap\RBBP7 gene have been introduced into flies, including a construct carrying a variant implicated in this disease. Heterologous rescue (functional complementation) is observed: wild-type human RBBP7 rescues male infertility in Caf1-55-deficient Drosophila; however, RBBP7 carrying the disease-implicated variant fails to rescue. (See the 'Disease-Implicated Variants' table, below.)
In Drosophila, animals homozygous for a null mutation of Caf1-55 typically die during the larval stage. In Drosophila males, knockdown of Caf1-55 in germ cells, using tissue-specific GAL4/UAS-RNAi, results in reduced underdeveloped testes and loss of male germline stem cells. Knockdown in the somatic cyst cells of the testis results in hyperproliferative testicular cells.
[updated Jan. 2024 by FlyBase; FBrf0222196]
Non-obstructive azoospermia (NOA) is defined as absence of any measurable level of sperm in semen, resulting from a defect in the production of spermatozoa in the testes. [from MedGen, Non-obstructive azoospermia; MedGen UID: 866757]
Non-obstructive azoospermia (NOA), or failure of spermatogenesis within the testis, is diagnosed in approximately 10% of infertile men. NOA may be due to a lack of appropriate stimulation by gonadotropins, in which case hormonal therapy is usually effective. A larger category of non-obstructive azoospermia consists of men with an intrinsic testicular impairment. In these cases, the primary approach is to improve the quantity and quality of sperm retrieved from the testis for use for in vitro fertilization (Kumar, 2013; PMCID:PMC3583162).
Observation of non-obstructive azoospermia (NOA).
Locus identified in large-scale analysis of X-linked mutations in men with non-obstructive azoospermia.
RBBP7 (RB binding protein 7, chromatin remodeling factor) is a core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. [from Uniprot:Q16576; 2022.11.02]
two to one: human gene to Drosophila gene.
High-scoring ortholog of human RBBP4 and RBBP7; (1 Drosophila to 2 human).