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Abstract
BackgroundJoubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation ‘the molar tooth sign’. Mutations in >27 genes cause JS, and mutations in 12 of these genes...
Highlights
Human ciliopathies embody a rapidly growing group of disorders characterised by dysfunction of the primary cilium, a membrane-bound bundle of microtubules that projects from the apical surface of most cells.[1]
Cilium length in fibroblasts from individuals with MKS1-related JS tends to be longer and more variable than controls To determine the cellular effects of the MKS1 mutations, we evaluated cilium number and length in primary skin fibroblasts from three of the affected individuals ( JBTS-10, JBTS-153 and JBTS-3504), a single fetus with Meckel-Gruber syndrome (MKS) (MKS-158; see online supplementary table S1 Subject: Khaddour ‘07:562), as well as the carrier parents of JBTS-3504 (Parent-3229 and Parent-1753) and healthy, non-carrier controls (Ctrl-10 and Ctrl-117 and fetal Ctrl-26153), using acetylated α-tubulin antibody to mark the ciliary axoneme and γ-tubulin antibody to mark the basal body
To determine whether defects were specific to loss of MKS1 function, we evaluated fibroblast lines from patients with JS with biallelic ARL13B (ARL13B-277)[31] and INPP5E (INPP5E-171)[41] mutations (See Material and Methods; Cell culture section)
Summary
Human ciliopathies embody a rapidly growing group of disorders characterised by dysfunction of the primary cilium, a membrane-bound bundle of microtubules that projects from the apical surface of most cells.[1]. The defining feature of JS is the molar tooth sign (MTS) on brain MRI: cerebellar vermis hypoplasia, thick, elongated and horizontally oriented superior cerebellar peduncles, and a deep interpeduncular fossa.[3] Clinically, JS is characterised by cognitive impairment, hypotonia, ataxia, abnormal eye movements, and episodic apnoea and/or tachypnoea in the neonatal period.[4] Variable additional features have been observed, including other central nervous system anomalies (agenesis of the corpus callosum, polymicrogyria, heterotopia and occipital encephalocele), chorioretinal coloboma, retinal dystrophy, cystic renal disease, hepatic fibrosis and polydactyly.[5,6,7,8,9,10,11,12,13,14,15,16]. The goals of this work are to describe the clinical features of MKS1related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS
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