Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

Abstract

Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic “molar tooth sign” on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients’ fibroblasts.

New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

“…We found an enrichment of genes with a role in centriolar replication and duplication, core processes in primary and motile cilia formation. Mutations in KIAA0753 cause the ciliopathies Joubert Syndrome and Orofaciodigital Syndrome 23 . Reduced airway motile cilia function impacting mucus clearance is a feature of COPD, but it has not been clear whether this is causal or the consequence of damage by external factors such as smoking or infection.…”

Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome

“…In addition, our patient had hypopituitarism without structural abnormalities of the pituitary gland on brain magnetic resonance imaging. Interestingly, growth hormone deficiency was frequently reported in JS caused by variants in two distinct genes (KIAA0753 and CELSR2) in association to absent, small or ectopic pituitary gland, strengthening the importance of ciliary function also in the development of the hypophysis and its function [17,18].…”

Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies

“…Previously, biallelic deleterious variants in KIAA0753 were reported in a patient with orofaciodigital syndrome (OFD) type 6 (OMIM currently classified as OFD15 [MIM:617127]) 12 and in two siblings with JBTS 14 . None of the clinical reports include skeletal dysplasia as a feature in their patients.…”

“…KIAA0753 protein has been identified as a centrosome component involved in centriole duplication and interacting with other centrosomal proteins 11 – 13 . Pathogenic variants in KIAA0753 have recently been found in association with JBTS 14 and orofaciodigital syndrome (OFD15 [MIM:617127]) 12 .…”