Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies

Abstract

The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.

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

“…The two common missense variants in KIAA0753 were within the credible set of new signal rs4796334. KIAA0753 , CEP72 and LRRC45 all encode proteins with a role in ciliogenesis or cilia maintenance 27–31 , and all are highly expressed in the airway epithelium 32 .…”

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

“…The two common missense variants in KIAA0753 were within the credible set of new signal rs4796334. KIAA0753 , CEP72 and LRRC45 all encode proteins with a role in ciliogenesis or cilia maintenance 22–26 , and all are highly expressed in the airway epithelium 27 .…”

A ciliopathy complex builds distal appendages to initiate ciliogenesis

“…Related to their roles in fundamental cellular processes such as cell division and intercellular communication, centriole dysfunction causes diverse human developmental disorders including ciliopathies and microcephaly (Nigg and Holland, 2018; Reiter and Leroux, 2017). For example, mutations in CEP90 ( Centrosomal protein of 90 kDa , also known as PIBF1 ), MNR ( MOONRAKER , also known as KIAA0753 or OFIP ) or OFD1 cause Joubert syndrome (JBTS), a ciliopathy characterized by brainstem and cerebellar malformations (Wheway et al, 2015; Shen et al, 2020; Hebbar et al, 2018; Stephen et al, 2017; Hammarsjö et al, 2017; Coene et al, 2009). Similarly, in many cancers, the number or structure of centrioles is dysregulated (Gönczy, 2015; Marteil et al, 2018).…”