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Biallelic variants in DNA2 cause microcephalic primordial dwarfism
Žygimantė Tarnauskaitė1, Louise S Bicknell1, Joseph A Marsh1
1MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Human Mutation
|May 3, 2019
Summary
Microcephalic primordial dwarfism (MPD) is linked to DNA2 gene mutations. These variants disrupt DNA replication and repair, causing severe growth reduction from early development.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Microcephalic primordial dwarfism (MPD) comprises rare single-gene disorders.
- Affected individuals exhibit extreme reductions in brain and body size early in development.
- MPD-associated genes are crucial for fundamental cellular processes like genome replication and repair.
Observation:
- Four MPD individuals with biallelic variants in the DNA2 gene were identified.
- DNA2 encodes an ATP-dependent helicase/nuclease essential for DNA replication and repair.
- Two intronic variants (c.1764-38_1764-37ins(53) and c.74+4A>C) were found to impair DNA2 transcript splicing.
Findings:
- A missense variant (c.1963A>G) affects a highly conserved residue in the ATP-dependent helicase domain.
- The substitution (p.Thr655Ala) is predicted to directly impact ATP/ADP binding by DNA2.
- These variants function as biallelic hypomorphic mutations, reducing DNA2 activity.
Implications:
- DNA2 is established as a novel disease gene for microcephalic primordial dwarfism.
- Understanding DNA2's role provides insights into MPD pathogenesis.
- This discovery opens avenues for potential therapeutic strategies targeting DNA replication and repair pathways.
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