A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis

Abstract

BackgroundHydranencephaly is a congenital anomaly leading to replacement of the cerebral hemispheres with a fluid-filled cyst. The goals of this work are to describe a novel autosomal-recessive syndrome that includes hydranencephaly (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly (MARCH)); to identify its genetic cause(s) and to provide functional insight into pathomechanism.MethodsWe used homozygosity mapping and exome sequencing to identify recessive mutations in a single family with three affected fetuses. Immunohistochemistry, RT-PCR and imaging in cell lines, and zebrafish models, were used to explore the function of the gene and the effect of the mutation.ResultsWe identified a homozygous nonsense mutation in CEP55 segregating with MARCH. Testing the effect of this allele on patient-derived cells indicated both a reduction of the overall CEP55 message and the production of a message that likely gives rise to a truncated protein. Suppression or ablation of cep55l in zebrafish embryos recapitulated key features of MARCH, most notably renal dysplasia, cerebellar hypoplasia and craniofacial abnormalities. These phenotypes could be rescued by full-length but not truncated human CEP55 message. Finally, we expressed the truncated form of CEP55 in human cells, where we observed a failure of truncated protein to localise to the midbody, leading to abscission failure and multinucleated daughter cells.Conclusions CEP55 loss of function mutations likely underlie MARCH, a novel multiple congenital anomaly syndrome. This association expands the involvement of centrosomal proteins in human genetic disorders by highlighting a role in midbody function.

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

“…During the publication process of present study, an article describing a truncating mutation in CEP55 as the likely cause of a novel syndrome MARCH was published . We do not have enough data to classify our fetuses to fulfill the criteria of MARCH syndrome, however, there are similar clinical signs between the studies.…”

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

“…We and others have shown that zebrafish can serve as robust direct models for craniofacial abnormalities observed in humans. 39,42,[48][49][50][51][52] We assessed the craniofacial patterning by measuring the angle of ceratohyal (CH) cartilage in ventral images acquired from 3 dpf larvae. We observed a significant increase of the CH angle in bptf CRISPR F0 mutants (102 versus 91 for F0 mutants versus controls; p % 0.0001, n ¼ 47-59 larvae/batch, repeated; Figure 2).…”

Involvement of the centrosomal protein 55 (cep55) gene in zebrafish head formation

“…Recently, a homozygous non-sense mutation in human CEP55 has been identified in a novel perinatal lethal syndrome, MARCH syndrome, with microretrognathia and limb contractures (Frosk et al, 2017). The researchers found that the temporal cortex was disorganized and that large numbers of neurons and glial cells were multinucleated cells in MARCH patient brain tissue.…”

“…Furthermore, CEP55 regulates the phosphoinositide 3-kinase (PI3K)/AKT pathway (Chen et al, 2009;Hwang et al, 2013), presumably leading to the promotion of tumorigenesis. Recently, a truncating mutation in human CEP55 has been identified | 643 Genes to Cells YANAGI et Al. in MARCH (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly) syndrome (Frosk et al, 2017). It is thought that aberrant expression of CEP55 is associated with tumorigenesis; however, the developmental function of CEP55 in vertebrates is not fully understood.…”