CEP55 – MARCH syndrome

CEP55 encodes a centrosomal protein essential for midbody abscission during cytokinesis. Biallelic loss-of-function variants in CEP55 underlie multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly (MARCH) syndrome, a severe autosomal-recessive disorder characterized by hydranencephaly, renal dysplasia, and cerebellar hypoplasia (CEP55; MARCH syndrome).

Genetic studies identified a homozygous nonsense allele in a consanguineous family with three affected fetuses, and compound heterozygous LoF/missense or homozygous splice variants in seven living individuals from five additional families, totaling ten probands with concordant clinical features (PMID:28264986; PMID:32100459). Variants comprise nonsense (n=4), frameshift (n=2), splice-site (n=1), and missense (n=4) changes, demonstrating a spectrum of biallelic alleles.

Inheritance is strictly autosomal recessive, with segregation demonstrated in six families (including three sibships and one multiplex fetus pedigree) and a total of four additional affected relatives beyond probands. The recurrent founder frameshift c.908del (p.Lys303fs) was observed in the Amish community (PMID:30622327).

Functional assays in patient‐derived cells reveal reduced CEP55 mRNA and production of a truncated protein failing to localize to the midbody, causing abscission failure and multinucleated cells. Zebrafish cep55l knockdown or CRISPR mutants recapitulate key MARCH phenotypes—renal dysplasia and cerebellar hypoplasia—which are rescued by full-length but not truncated human CEP55 message (PMID:28264986).

Mechanistic studies highlight loss-of-function as the pathogenic mechanism. A cep55 nonsense mutant in zebrafish shows early apoptosis and cell-cycle defects with destabilized Akt, partially rescued by activated PIK3CA or AKT1, and proteasome inhibition, linking CEP55 to PI3K/AKT pathway regulation (PMID:25667221). Additional structural work on the ubiquitin-binding domains (NOA and ZF) of CEP55 underscores its non-degradative ubiquitin signaling role during abscission, providing a molecular basis for LOF mutations leading to MARCH syndrome (PMID:31605944).

No studies to date refute the association or implicate alternative inheritance patterns. The collective genetic and functional data support a strong gene-disease relationship, with autosomal-recessive CEP55 variants reliably predicting MARCH syndrome in the prenatal or early postnatal setting.

Key Take-home: Biallelic CEP55 LOF variants cause a clinically recognizable, autosomal-recessive MARCH syndrome via disrupted midbody abscission and PI3K/AKT signaling, supporting diagnostic testing and genetic counseling.

References

• Journal of medical genetics • 2017 • A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis. PMID:28264986
• American journal of medical genetics. Part A • 2020 • Expanding the spectrum of CEP55‐associated disease to viable phenotypes. PMID:32100459
• FASEB journal • 2015 • Cep55 regulates embryonic growth and development by promoting Akt stability in zebrafish. PMID:25667221
• iScience • 2019 • Two NEMO-like Ubiquitin-Binding Domains in CEP55 Differently Regulate Cytokinesis. PMID:31605944
• European journal of human genetics : EJHG • 2019 • An Amish founder variant consolidates disruption of CEP55 as a cause of hydranencephaly and renal dysplasia. PMID:30622327

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