Murine model indicates 22q11.2 signaling adaptor CRKL is a dosage-sensitive regulator of genitourinary development

Abstract

The spectrum of congenital anomalies affecting either the upper tract (kidneys and ureters) or lower tract (reproductive organs) of the genitourinary (GU) system are fundamentally linked by the developmental origin of multiple GU tissues, including the kidneys, gonads, and reproductive ductal systems: the intermediate mesoderm. Although ∼31% of DiGeorge/del22q11.2 syndrome patients exhibit GU defects, little focus has been placed on the molecular etiology of GU defects in this syndrome. Among del22q11.2 patients exhibiting GU anomalies, we have mapped the smallest relevant region to only five genes, including encodes a src-homology adaptor protein implicated in mediating tyrosine kinase signaling, and is expressed in the developing GU-tract in mice and humans. Here we show that mutant embryos exhibit gene dosage-dependent growth restriction, and homozygous mutants exhibit upper GU defects at a microdissection-detectable rate of 23%. RNA-sequencing revealed that 52 genes are differentially regulated in response to uncoupling from its signaling pathways in the developing kidney, including a fivefold up-regulation of, a known regulator of nephron progenitor differentiation. Additionally, heterozygous adult males exhibit cryptorchidism, lower testis weight, lower sperm count, and subfertility. Together, these data indicate that is intimately involved in normal development of both the upper and lower GU tracts, and disruption of contributes to the high incidence of GU defects associated with deletion at 22q11.2.

Chromosomal microarray analysis in fetuses with congenital anomalies of the kidney and urinary tract: A prospective cohort study and meta‐analysis

“…In this meta‐analysis, three of the six fetuses with 22q11.2 microdeletion presented with associated cardiac defects. Recently, a recurrent 370‐kb deletion at the 22q11.2 locus was reported to be the driver of kidney defects in both syndromic and isolated CAKUT, with the haploinsufficiency of CRKL (OMIM 602007) as the critical genetic driver . Thus, we hypothesized that the 22q11.2 deletion was the cause of CAKUT in our cases.…”

Essential role of theCrkfamily-dosage in DiGeorge-like anomaly and metabolic homeostasis

“…Although haploinsufficiency of TBX1 has been strongly implicated in DGS, deficiency of mouse Crkl alone also affects normal development of anterior/frontal structures, including facial features, great arteries, heart, thymus, and parathyroid, as well as posterior structures, including genitourinary (GU) tissues, as collectively manifested as a condition that resembles DiGeorge anomaly (Guris et al, 2001;Racedo et al, 2015;Haller et al, 2017;Lopez-Rivera et al, 2017). CRKL point mutations have also been identified among a large cohort of patients with renal agenesis or hypodysplasia (Lopez-Rivera et al, 2017).…”

“…CRKL point mutations have also been identified among a large cohort of patients with renal agenesis or hypodysplasia (Lopez-Rivera et al, 2017). A distal region of the common deletion that includes CRKL has been linked to GU defects among 22q11.2DS patients, and haploinsufficiency of Crkl results in abnormal GU development in mice (Haller et al, 2017;Lopez-Rivera et al, 2017). Although CRKL coding mutations have not been linked to DGS without a 22q11 deletion, a recent study has identified non-coding mutations predicted to affect CRKL expression in the hemizygous region of the common 22q11 deletion with conotruncal defects (Zhao et al, 2020).…”

Sequence variant in the CDC42BPB gene is potentially associated with Mullerian duct anomalies

“…That indicates the role of genetic factors in the pathogenesis of MDAs, but the pathogenic genes are still unclear. Previous studies have found that mutations or copy number variations (CNVs) in the genes, including TBX6 , HNF1B , HOXA13 , HOXA10 , LHX1 , PBX1 , WNT9B , EMX2 , CRKL and TP63 , are associated with MDAs.…”