The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• DROSHA is a key ribonuclease in the Microprocessor complex, essential for the initial step of microRNA (miRNA) biogenesis.
• Mendelian diseases associated with DROSHA have not been previously identified.

Purpose of the Study:

• To investigate the potential role of DROSHA variants in severe neurodevelopmental disorders.
• To functionally characterize identified DROSHA variants using model organisms.

Main Methods:

• Clinical evaluation of two individuals with profound intellectual disability, epilepsy, microcephaly, and dysmorphic features.
• Genetic analysis to identify de novo heterozygous variants in DROSHA.
• Functional studies in Drosophila melanogaster (fruit flies) and Caenorhabditis elegans (worms) to assess the impact of DROSHA variants.

Main Results:

• Two individuals presented with severe phenotypes and carried damaging de novo heterozygous variants in DROSHA.
• Functional assays in flies indicated that one variant (p.Asp1219Gly) acts as a strong loss-of-function allele, while another (p.Arg1342Trp) is less detrimental.
• Worm studies mimicking the p.Asp1219Gly variant resulted in loss of miRNA expression and heterochronicity, confirming a loss-of-miRNA phenotype.

Conclusions:

• The identified de novo heterozygous variants in DROSHA are damaging and likely cause severe nervous system phenotypes.
• This study establishes a link between DROSHA dysfunction and Mendelian neurodevelopmental disorders.
• Functional studies in model organisms are crucial for validating the pathogenicity of genetic variants.