A novel contiguous gene deletion ofAVPR2andARHGAP4genes in male dizygotic twins with nephrogenic diabetes insipidus and intellectual disability

Transgenic mouse models of defective urinary concentrating ability produced by deletion of various membrane transport or receptor proteins, including aquaporin-2 (AQP2), are associated with neonatal mortality from polyuria. Here, we report an inducible mouse model of AQP2 gene deletion with severe polyuria in adult mice. LoxP sequences were inserted into introns 1 and 2 in the mouse AQP2 gene by homologous recombination in embryonic stem cells. Mating of germ-line AQP2-loxP mice with tamoxifen-inducible Cre-expressing mice produced offspring with inducible homozygous Cre-AQP2-loxP, which had a normal phenotype. Tamoxifen injections over 10 days resulted in AQP2 gene excision, with undetectable full-length AQP2 transcript in kidney and a >95% reduction in immunoreactive AQP2 protein. Urine osmolality decreased from ∼2,000 to <500 mosmol/kgH2O after 4–5 days, with urine output increasing from 2 to 25 ml/day. Urine osmolality did not increase after water deprivation. Interestingly, AQP3 protein expression in the collecting duct was increased by about fivefold after AQP2 gene excision. Mild renal damage was seen after 6 wk of polyuria, with collecting duct dilatation, yet normal creatinine clearance and serum chemistries. These results establish the first adult model of nephrogenic diabetes insipidus (NDI) caused by AQP2 deficiency, with daily urine output comparable to body weight, although remarkable preservation of renal function compared with non-inducible NDI models.

Download Full-text

Macrocerebellum, epilepsy, intellectual disability, and gut malrotation in a child with a 16q24.1-q24.2 contiguous gene deletion

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.36569 ◽

2014 ◽

Vol 164 (8) ◽

pp. 2062-2068 ◽

Cited By ~ 4

Author(s):

Andrea H. Seeley ◽

Mark A. Durham ◽

Mark A. Micale ◽

Jeffrey Wesolowski ◽

Bradley R. Foerster ◽

...

Keyword(s):

Intellectual Disability ◽

Gene Deletion ◽

Contiguous Gene

Download Full-text

The Largest Germline Heterozygous Deletion Encompassing Potocki–Shaffer and WAGR Syndromes Loci to Date: A Case Report

Neuropediatrics ◽

10.1055/s-0041-1740357 ◽

2021 ◽

Author(s):

Geoffroy Delplancq ◽

Mohamed Abdelatif Boukebir ◽

Daniel Amsallem ◽

Laurent Thines ◽

Virginie Rozé ◽

...

Keyword(s):

Case Report ◽

Intellectual Disability ◽

High Resolution ◽

Array Comparative Genomic Hybridization ◽

Gene Deletion ◽

Comparative Genomic ◽

Prenatal Period ◽

Heterozygous Deletion ◽

Multiple Exostoses ◽

Contiguous Gene

AbstractPotocki–Schaffer syndrome includes multiple exostoses, parietal foramina, and variable developmental delay/intellectual disability. It is associated with a heterozygous deletion of the 11p12p11.2 region. In some cases, the deletion extends to the WAGR locus (11p13p12). We describe here a 9-month-old girl harboring the largest germline heterozygous deletion characterized so far. Oligohydramnios and parietal foramina were noticed during pregnancy. No patient has been diagnosed before with concomitance of these two syndromes during the prenatal period. Cytogenetic diagnosis was anticipated on basis of clinical and radiological signs. Postnatal conventional karyotype confirmed an interstitial 11p deletion: 46,XX,del(11)(p11.2p15.1). Array-comparative genomic hybridization characterized a 29.6 Mb deletion. Our case illustrates the interest of high-resolution genomic approaches to correlate adequately clinical phenotypes with specific genes in suspected contiguous gene deletion syndromes.

Download Full-text