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Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 to Treat Neuromuscular Diseases in Rodents
Published on: August 10, 2018
The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder
Scott Barish1,2, Mumine Senturk1,2,3,4, Kelly Schoch5
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss of imaginal discs in the larva. Loss of drosha in eye clones causes small and rough eyes in adult flies. One of the identified DROSHA variants (p.Asp1219Gly) behaves as a strong loss-of-function allele in flies, while another variant (p.Arg1342Trp) is less damaging in our assays. In worms, a knock-in that mimics the p.Asp1219Gly variant at a worm equivalent residue causes loss of miRNA expression and heterochronicity, a phenotype characteristic of the loss of miRNA. Together, our data show that the DROSHA variants found in the individuals presented here are damaging based on functional studies in model organisms and likely underlie the severe phenotype involving the nervous system.
Insights
Damaging variants in the DROSHA gene, crucial for microRNA (miRNA) biogenesis, are linked to severe neurodevelopmental disorders. Functional studies in model organisms confirm these variants disrupt miRNA production and cause disease phenotypes.
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.
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