Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr)2161B.CA1C2Ove mouse model

Abstract

Nephronophthisis-related ciliopathies (NPHP-RC) are a group of disorders that present with end-stage renal failure in childhood/adolescence, kidney cysts, retinal degeneration, and cerebellar hypoplasia. One disorder that shares clinical features with NPHP-RC is Bardet-Biedl Syndrome (BBS). Serologically defined colon cancer antigen 8 (SDCCAG8; also known as NPHP10 and BBS16) is an NPHP gene that is also associated with BBS. To better understand the patho-mechanisms of NPHP and BBS caused by loss of SDCCAG8 function, we characterized an SDCCAG8 mouse model (Sdccag8Tn(sb-Tyr)2161B.CA1C2Ove) generated by Sleeping Beauty Transposon (SBT)-mediated insertion mutagenesis. Consistent with the previously reported, independent SDCCAG8 mouse models, our mutant mice display pre-axial polydactyly in their hind limbs. In addition, we report patterning defects in the secondary palate, brain abnormalities, as well as neonatal lethality associated with developmental defects in the lung in our mouse model. The neonatal lethality phenotype is genetic background dependent and rescued by introducing 129S6/SvEvTac background. Genetic modifier(s) responsible for this effect were mapped to a region between SNPs rs3714172 and rs3141832 on chromosome 11. While determining the precise genetic lesion in our mouse model, we found that SBT insertion resulted in a deletion of multiple exons from both Sdccag8 and its neighboring gene Akt3. We ascribe the patterning defects in the limb and the secondary palate as well as lung abnormalities to loss of SDCCAG8, while the developmental defects in the brain are likely due to the loss of AKT3. This mouse model may be useful to study features not observed in other SDCCAG8 models but cautions are needed in interpreting data.

Genome-Wide Analyses Reveal Genetic Convergence of Prolificacy between Goats and Sheep

“…Another PSG, SDCCAG8 , is a risk gene for Bardet–Biedl syndrome, which is primarily characterized by postaxial polydactyly, hypogonadotropic hypogonadism, and/or genitourinary malformations, and secondly characterized by polycystic ovary syndrome [ 35 ]. SDCCAG8 is a candidate gene for hind limb and rib cage malformations in mice [ 36 , 37 ] and teat number in pigs [ 38 ]. Interestingly, BMPR1B , a major gene for sheep LS, plays important roles in both chondrogenesis and embryogenesis [ 39 , 40 ], indicating the pleiotropism of candidate genes for bone formation and reproduction.…”

ABbs5mouse model reveals pituitary cilia contributions to developmental abnormalities

“…In mice, it has been reported that phenotypes associated with mutations in other Bbs genes are also affected by genetic background (19). Previous reports of background-dependent lethality in BBS mutant mice have been attributed to neural tube closure defects and pulmonary developmental defects (20,21). During embryo isolations, we never observed neural tube closure defects and…”

Latest Advances for the Sleeping Beauty Transposon System: 23 Years of Insomnia but Prettier than Ever

“…This has been directly done for various cancer models induced by SB‐mediated oncogene transposition including sarcomatoid carcinoma, [ 115,116 ] prostate cancer, [ 117 ] hepatocellular carcinoma, [ 118 ] peritoneal carcinomatosis, [ 119 ] glioma, [ 120 ] HPV16 + oral tumors [ 121 ] but also for non‐cancer‐related disorders such as spinocerebellar ataxia type‐1, [ 122 ] age‐related renal pathologies, [ 123 ] and nephronophthisis‐related ciliopathies. [ 124 ] Additionally, with increasing demand of gene therapies and a climbing number of successful transitions of preclinical research into clinical trials and approved medicinal products, SB's attractive features have further widened its implementation in the fields of basic research and preclinical studies ( Table 1 ).…”