A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal
M-L Bondeson1, K Ericson1,2, S Gudmundsson1
1Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.
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.
Insights
Genetic mutations in CEP55 cause Meckel-Gruber syndrome, a lethal ciliopathy. This study identifies a CEP55 mutation in affected fetuses, highlighting its crucial role in embryonic development and disease.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Biology
Background:
- Ciliopathies are genetic disorders arising from mutations in genes governing the cilium-centrosome complex.
- Meckel-Gruber syndrome (MKS) is a severe, lethal autosomal recessive ciliopathy with diverse clinical features, including renal cystic dysplasia, occipital encephalocele, and polydactyly.
- While several genes are linked to MKS, the genetic basis for some cases remains unknown.
Purpose of the Study:
- To identify the genetic cause of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses.
- To investigate the role of identified genes in embryogenesis and disease development.
Main Methods:
- Whole-exome sequencing (WES) was employed to analyze the genetic makeup of affected fetuses.
- RNA studies and histopathological analysis were conducted for further characterization.
Main Results:
- WES identified a homozygous nonsense mutation (c.256C>T, p.Arg86*) in the CEP55 (centrosomal protein of 55 kDa) gene in the affected fetus.
- This CEP55 variant segregated within the family and has been previously observed in carriers at low frequencies.
- CEP55 is essential for mid-body formation during cell division (cytokinesis).
Conclusions:
- The findings implicate CEP55 as a novel gene associated with Meckel-Gruber syndrome.
- This study expands the spectrum of centrosomal proteins involved in human ciliopathies.
- CEP55 plays a critical role in human embryogenesis and the development of MKS.
Related Concept Videos
02:27Nonsense-mediated mRNA Decay
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
02:23Master Transcription Regulators
02:20Cohesins
Cohesin complexes in Meiotic Division
Meiosis involves two distinct rounds of chromosomal segregation and cell divisions— Meiosis I followed by Meiosis II – producing four daughter cells. Meiosis I includes the separation of...
01:20Mismatch Repair
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
01:39Mutations
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...