A nonsense mutation in CEP55 defines a new locus for a Meckel‐like syndrome, an autosomal recessive lethal fetal ciliopathy

Abstract

Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole-exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with 2 affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.

Cytokinetic furrowing and abscission dynamics during brain development revealed by live imaging

“…The polarized form of cytokinesis in embryonic cortical NSCs is poorly understood, but may influence the segregation of organelles and apical fate determinants to daughter cells as they make fate choices. Recent findings that mutations in Kif20b and other midbody genes cause microcephaly in humans and mice suggest that brain development is especially sensitive to defects in cytokinesis (26,(35)(36)(37)(38)(39). To elucidate these issues, we developed methods to quantitatively analyze furrowing and abscission in NSCs of the developing cerebral cortex.…”

Cep55 overexpression causes male‐specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling

“…Using a zebra fish model, they demonstrated that loss of function of cep55 mimicked the features of MARCH observed in human patients, therefore establishing a strong connection of the protein with a novel multiple congenital anomaly syndrome. Bondeson et al (46) showed that loss of Cep55 is associated with a ciliopathic lethal autosomal recessive syndrome called MKS, characteristics of which involve renal cystic dysplasia, occipital encephalocele, and polydactyly.…”

“…Furthermore, we showed that Akt was destabilized in the homozygous mutants, which was partially rescued by providing either constitutively activated PI3K-CA or AKT1 expression. In addition, 2 recent studies have emphasized the connection between CEP55 loss and genetic diseases like multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH) (45) and Meckel-Gruber syndrome (MKS) (46), characterized by the presence of multiple congenital anomalies.…”

Regulation of cytokinesis during corticogenesis: focus on the midbody

“…Abscission, the process through which the membrane connecting the two newly generated cells is severed resulting in physical separation of the siblings, concludes cytokinesis . Few studies have directly examined cytokinesis in NSCs and RGCs during corticogenesis despite mutations of cytokinesis‐regulating proteins in several neurodevelopmental disorders (e.g., microcephaly) . In polarized tissues such as the telencephalon, the orientation of division may be critical to maintain overall tissue structure and daughter cell identity .…”