Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences...

Area of Science:

• Genetics
• Cell Biology
• Developmental Biology

Background:

• Ciliopathies are genetic disorders stemming from primary cilium defects, impacting crucial developmental signaling pathways.
• These disorders encompass conditions like orofaciodigital syndromes (OFDS), short rib polydactyly syndromes, and Jeune asphyxiating thoracic dystrophy.
• Previous research linked mutations in the C2CD3 gene to a specific OFDS subtype (OFD14) characterized by microcephaly and cerebral malformations.

Purpose of the Study:

• To investigate novel compound heterozygous C2CD3 mutations in a family presenting with a distinct clinical phenotype.
• To analyze the functional consequences of these C2CD3 mutations on cilia formation and basal body maturation.
• To elucidate the role of C2CD3 in basal body maturation and its interaction with other proteins like CEP164.

Main Methods:

• Genetic sequencing to identify mutations in the C2CD3 gene.
• Clinical evaluation of affected fetuses to characterize the phenotype.
• Analysis of fibroblast cultures to assess cilia formation and basal body protein recruitment.

Main Results:

• Identified novel compound heterozygous C2CD3 mutations in two fetuses with skeletal dysplasia but no microcephaly.
• Fibroblast cultures showed a reduced ability to form cilia, confirming C2CD3's role in ciliogenesis.
• C2CD3 appears crucial for basal body maturation, though CEP164 recruitment is not solely sufficient for ciliogenesis in its absence.

Conclusions:

• C2CD3 mutations can lead to ciliopathies with diverse clinical presentations, including skeletal dysplasia.
• C2CD3 plays a critical role in basal body maturation, essential for primary cilium assembly.
• The findings suggest a complex mechanism for basal body maturation and axonemal extension in C2CD3-deficient backgrounds.