Faculty Opinions recommendation of Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome.

2020 ◽  
Author(s):  
Alejandro Schaffer
Keyword(s):  
Genetic Modifier ◽  
Joubert Syndrome ◽  
Mouse Genetics

scholarly journals Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

2019 ◽  
Vol 117 (2) ◽  
pp. 1113-1118 ◽  
Author(s):  
Simon A. Ramsbottom ◽  
Peter E. Thelwall ◽  
Katrina M. Wood ◽  
Gavin J. Clowry ◽  
Laura A. Devlin ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Phenotypic Variability ◽  
Genetic Modifier ◽  
Joubert Syndrome ◽  
Mouse Genetics ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Genetic Associations ◽  
Disease Heterogeneity ◽  
Large Patient

Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.

scholarly journals INPP5E regulates phosphoinositide-dependent cilia transition zone function

2016 ◽  
Vol 216 (1) ◽  
pp. 247-263 ◽  
Author(s):  
Jennifer M. Dyson ◽  
Sarah E. Conduit ◽  
Sandra J. Feeney ◽  
Sandra Hakim ◽  
Tia DiTommaso ◽  
...  
Keyword(s):  
Transition Zone ◽  
Hedgehog Signaling ◽  
Joubert Syndrome ◽  
Mouse Genetics ◽  
Molecular Organization ◽  
Scaffolding Proteins ◽  
Inositol Polyphosphate ◽  
Wild Type ◽  
Essential Point ◽  
Phosphoinositide Signaling

Human ciliopathies, including Joubert syndrome (JBTS), arise from cilia dysfunction. The inositol polyphosphate 5-phosphatase INPP5E localizes to cilia and is mutated in JBTS. Murine Inpp5e ablation is embryonically lethal and recapitulates JBTS, including neural tube defects and polydactyly; however, the underlying defects in cilia signaling and the function of INPP5E at cilia are still emerging. We report Inpp5e−/− embryos exhibit aberrant Hedgehog-dependent patterning with reduced Hedgehog signaling. Using mouse genetics, we show increasing Hedgehog signaling via Smoothened M2 expression rescues some Inpp5e−/− ciliopathy phenotypes and “normalizes” Hedgehog signaling. INPP5E’s phosphoinositide substrates PI(4,5)P2 and PI(3,4,5)P3 accumulated at the transition zone (TZ) in Hedgehog-stimulated Inpp5e−/− cells, which was associated with reduced recruitment of TZ scaffolding proteins and reduced Smoothened levels at cilia. Expression of wild-type, but not 5-phosphatase-dead, INPP5E restored TZ molecular organization and Smoothened accumulation at cilia. Therefore, we identify INPP5E as an essential point of convergence between Hedgehog and phosphoinositide signaling at cilia that maintains TZ function and Hedgehog-dependent embryonic development.

468: Polymorphic CA Repeats in IGF-I Gene is a Common Genetic Modifier in the Etiology of Prostate Cancer and Benign Prostatic Hyperplasia

2004 ◽  
Vol 171 (4S) ◽  
pp. 125-125
Author(s):  
Lizhong Wang ◽  
Kazunari Sato ◽  
Norihiko Tsuchiya ◽  
Chikara Ohyama ◽  
Shigeru Satoh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Benign Prostatic Hyperplasia ◽  
Genetic Modifier ◽  
Prostatic Hyperplasia ◽  
Igf I ◽  
I Gene

Joubert syndrome: long-term follow-up

2004 ◽  
Vol 46 (10) ◽  
Author(s):  
Peter R Hodgkins ◽  
Christopher M Harris ◽  
Fatima S Shawkat ◽  
Dorothy A Thompson ◽  
Kling Chong ◽  
...  
Keyword(s):  
Joubert Syndrome ◽  
Long Term Follow Up

Three Cases of Joubert Syndrome in a Consanguineous Syrian Family and a Interesting Case of Multinational Collaboration

2021 ◽  
Author(s):  
Davor Petrović ◽  
Vida Čulić ◽  
Zofia Swinderek-Alsayed
Keyword(s):  
Low Income ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Joubert Syndrome ◽  
Interesting Case ◽  
Low Income Countries ◽  
Ocular Motor ◽  
Quality Health Care ◽  
Quality Health ◽  
Motor Apraxia

AbstractJoubert syndrome (JS) is a rare congenital, autosomal recessive disorder characterized by a distinctive brain malformation, developmental delay, ocular motor apraxia, breathing abnormalities, and high clinical and genetic heterogeneity. We are reporting three siblings with JS from consanguineous parents in Syria. Two of them had the same homozygous c.2172delA (p.Trp725Glyfs*) AHI1 mutation and the third was diagnosed prenatally with magnetic resonance imaging. This pathogenic variant is very rare and described in only a few cases in the literature. Multinational collaboration could be of benefit for the patients from undeveloped, low-income countries that have a low-quality health care system, especially for the diagnosis of rare diseases.

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