EP 144: Research Roundup with Dr. Veera: breakthroughs in developmental disorders, Parkinson's, SLE, and Alzheimer's
July 25, 2024
Join us as we welcome back Dr. Veera Rajagopal, a discovery scientist at Regeneron with an interest in human genetics and drug target discovery in neuroscience and psychiatry. If you’re a regular listener of The Genetics Podcast, you are likely familiar with Dr. Veera’s annual round-up episodes. This year, we are excited to announce quarterly episodes with Dr. Veera, where he and Patrick walk you through the latest developments in genetics, drug discovery, and precision medicine throughout the year. This quarter’s episode will dive into the discovery of a recurrent de novo mutation in a noncoding region linked to neurodevelopmental disorders, the role of RAB32 in Parkinson's disease (PD), insights into monogenic conditions like systemic lupus erythematosus, and new perspectives on Alzheimer's genetics. Tune in now, and don’t forget to check out Veera’s substack, GWAS Stories, and his Twitter, @doctorveera.
0:00 Introduction
1:40 A recurrent de novo mutation in a noncoding region of a small nucleolar RNA gene that has been identified as one of the most common causes of neurodevelopmental disorders
- This pathogenic variant escaped notice for years because it was not located in a protein coding region of the genome
- It now shows potential as a target for various therapeutic developments for children with developmental disorders
- See the original paper here: De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders
20:30 A new gene, RAB32, linked to Parkinson’s disease through exome sequencing of families impacted by PD
- Direct interactions with the LRRK2 gene through its armadillo domain, resulting in a gain of function missense mutation
- How RAB32 was discovered as a significant mutation in PD research
- The strong therapeutic implications of RAB32 and LRRK2
- See original papers: RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses and Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease
35:30 Gaining insights from rare, monogenic conditions: A monogenic cause of early onset systemic lupus erythematosus (SLE)
- Making discoveries by following a biological thread, a rare privilege enjoyed by few fields like immunology
- See original paper here: Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus
- A related paper from two years ago on SLE and the TLR7 gene: TLR7 gain-of-function genetic variation causes human lupus
49:30 Alzheimer’s disease: Old genes, new insights
- Redefining research goals to make better sense of old discoveries, in addition to making new discoveries
- deCODE’s previous work on the homozygosity deficit inference
- APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease
- Homozygosity for R47H in TREM2 and the Risk of Alzheimer’s Disease
59:00 Closing remarks
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