Biallelic variants in DNAH10 are associated with skeletal developmental abnormalities and ciliary dysfunction.

Area of Science:

• Genetics
• Cell Biology
• Developmental Biology

Background:

• Primary cilia are crucial for skeletal development, coordinating signaling in osteoblasts and chondrocytes.
• Skeletal ciliopathies are linked to ~40 genes, but more causative genes are needed.
• DNAH10's role in primary cilia is unknown, despite its known function in motile cilia.

Purpose of the Study:

• Investigate the role of DNAH10 in skeletal development.
• Determine if DNAH10 variants cause skeletal abnormalities.

Main Methods:

• Whole-exome sequencing identified biallelic DNAH10 variants in two individuals.
• In vitro assays assessed DNAH10 variant effects on protein levels.
• Generated Dnah10 knockout mice to study skeletal phenotypes and mechanisms.

Main Results:

• Biallelic DNAH10 variants were found in individuals with skeletal abnormalities.
• In vitro, variants reduced DNAH10 protein abundance.
• Dnah10 knockout mice showed polydactyly, impaired cartilage development, and abnormal ossification.
• DNAH10 loss affected primary cilia, Hedgehog signaling, osteoblast differentiation, and chondrocyte maturation.

Conclusions:

• DNAH10 is a candidate gene for skeletal developmental abnormalities and ciliary dysfunction.
• DNAH10 plays a significant role in primary cilia-mediated skeletal development.
• This highlights a previously unrecognized function of DNAH10 in skeletal development.