Inactivation of DRG1, encoding a translation factor GTPase, causes a recessive neurodevelopmental disorder

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Developmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a conserved GTPase involved in translation.
• DRG1 expression is elevated in the developing central nervous system, but pathogenic germline variants were previously unidentified.

Purpose of the Study:

• To characterize the clinical and biochemical consequences of germline DRG1 variants.
• To define a new Mendelian disorder associated with DRG1 deficiency.

Main Methods:

• Collation of clinical data from 4 individuals with germline DRG1 variants.
• In silico, in vitro, and cell-based studies to assess variant pathogenicity.
• Targeted inactivation of mouse Drg1.

Main Results:

• Identification of private germline DRG1 variants (3 stop-gained, 1 missense) causing a recessive neurodevelopmental disorder.
• Affected individuals presented with global developmental delay, microcephaly, short stature, and craniofacial anomalies.
• Loss-of-function variants disrupted DRG1 mRNA/protein stability, impaired GTPase activity, and compromised ZC3H15 binding; mouse Drg1 inactivation led to lethality.

Conclusions:

• A novel Mendelian disorder of DRG1 deficiency is defined.
• Highlights the critical role of DRG1 in mammalian development.
• Underscores the significance of translation factor GTPases in human physiology and homeostasis.