Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development
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RESEARCH ARTICLE
Open Access
Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development L. Powell1†, M. Barroso-Gil1†, G. J. Clowry2, L. A. Devlin1, E. Molinari1, S. A. Ramsbottom1, C. G. Miles1 and J. A. Sayer1,3,4*
Abstract Background: Joubert syndrome and related disorders (JSRD) and Jeune syndrome are multisystem ciliopathy disorders with overlapping phenotypes. There are a growing number of genetic causes for these rare syndromes, including the recently described genes ARL3 and CEP120. Methods: We sought to explore the developmental expression patterns of ARL3 and CEP120 in humans to gain additional understanding of these genetic conditions. We used an RNA in situ detection technique called RNAscope to characterise ARL3 and CEP120 expression patterns in human embryos and foetuses in collaboration with the MRC-Wellcome Trust Human Developmental Biology Resource. Results: Both ARL3 and CEP120 are expressed in early human brain development, including the cerebellum and in the developing retina and kidney, consistent with the clinical phenotypes seen with pathogenic variants in these genes. Conclusions: This study provides insights into the potential pathogenesis of JSRD by uncovering the spatial expression of two JSRD-causative genes during normal human development. Keywords: CEP120, ARL3, Foetus, Development, Retina, Kidney, Brain, RNAscope
Background Joubert syndrome and related disorders (JSRD) are a group of autosomal inherited ciliopathies that are characterised as a cerebello-retinal-renal phenotype, and have an incidence rate of 1:80,000–100,000 live births [1–3]. The hallmark brain phenotype is a “molar tooth sign” shown on axial brain MRI, caused by cerebellar vermis hypoplasia and other mid and hindbrain * Correspondence: [email protected] † Powell L and Barroso-Gil M are joint first authors † L. Powell and M. Barroso-Gil contributed equally to this work. 1 Translational and Clinical Research Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK 3 The Newcastle Hospitals NHS Foundation Trust, Freeman Road, Newcastle upon Tyne NE7 7DN, UK Full list of author information is available at the end of the article
malformations [4]. These defects often cause symptoms of hypotonia, ataxia and intellectual disability in patients [5]. The retinal and renal phenotypes associated with JSRD have a lower incidence rate and vary in severity. Renal disorders occur in ~ 25% of patients, often presenting as corticomedullary cysts, interstitial fibrosis, or tubulointerstitial kidney disease [5]. The renal component is progressive and can lead to end-stage renal disease [6]. Ocular phenotypes of retinitis dystrophy, retinitis pigmentosa, oculomotor apraxia, and ptosis are common in patients, and as with the renal aspects of JSRD are often progressive in nature [7]. Currently, there are more than 35 genes that are known to cause JSRD (https://www.omim.org/phenotypicSeries/PS213300). The syndrome is caused by defects
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