This report describes a form of X-linked 46,XY gonadal dysgenesis. The human gene implicated in this disease is STARD8, which encodes a Rho GTPase activating protein characterized by a lipid transfer domain. There is a single orthologous gene in Drosophila, cv-c, for which multiple genetic reagents are available, including hypomorphic and amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis. Dmel\cv-c is ortholgous to two additional human genes, DLC1 and STARD13.
Animals homozygous for Dmel\cv-c loss-of-function mutations typically die during embryonic stages with multiple morphological defects, including failure of the Malpighian tubules to elongate. Homozygous mutant male embryos have abnormal testes containing germ cells that are not surrounded by the gonadal mesoderm; embryonic female gonads appear normal. Roles of the different protein domains of cv-c have been investigated and compared to the human genes.
UAS constructs of human Hsap\STARD8 have been introduced into flies, carrying either the wild-type gene or one carrying a variant implicated in this disease. Using the wild-type human gene, heterologous rescue (functional complementation) has been demonstrated for loss-of-function cv-c Malpighian tubule defects and for loss-of-function phenotypes of the testis mesoderm. The Hsap\STARD8 gene carrying a disease-implicated variant fails to rescue; see the 'Disease-Implicated Variants' table below.
[updated Jan. 2023 by FlyBase; FBrf0222196]
Abnormal gonadogenesis in human 46,XY individuals leads to under-masculinization, resulting in incomplete sexual characteristics at birth. Patients with complete gonadal dysgenesis present female external genitalia and hypogonadotropic hypogonadism with lack of secondary sex characteristics (Rocha et al., 2011; pubmed:21982289).
This form of gonadal dysgenesis exhibits X-linked recessive inheritance; it has been observed in male offspring of mothers heterozygous for the disease-implicated STARD8 variant (Sotillos et al., 2022; pubmed: 36326091; FBrf0255075).
STARD8 gene encodes a member of a subfamily of Rho GTPase activating proteins that contain a steroidogenic acute regulatory protein related lipid transfer domain. The encoded protein localizes to focal adhesions and may be involved in regulating cell morphology. [Gene Cards, STARD8; 2023.01.11]
Many to one: 3 human genes to 1 Drosophila gene.
Moderate-scoring ortholog of human DLC1, STARD13 and STARD8 (1 Drosophila to 3 human).
