Identification of mutation in GTPBP2 in patients of a family with neurodegeneration accompanied by iron deposition in the brain

Abstract

We aimed to identify the genetic cause of a neurologic disorder accompanied with mental deficiency in a consanguineous family with 3 affected siblings by linkage analysis and exome sequencing. Iron accumulation in the brain of the patients was a notable phenotypic feature. A full-field electroretinography revealed generalized dysfunction of photoreceptors, bipolar cells, and amacrine cells. A splice site mutation in GTPBP2 that encodes GTP-binding protein 2 was identified in the patients and considered possible cause of their disease. The mutation was empirically shown to cause deletion of exon 9 of the gene and result in production of a truncated protein-lacking conserved C-terminus domains. GTPBP2 is a member of the GTPase superfamily of proteins. A recent report of identification of another splice site mutation in GTPBP2 in mice that causes neurodegeneration, and retinal damage provides supportive evidence for our finding. The conditions in the affected individuals of the family studied may define a novel form of neurodegeneration with brain iron accumulation, and GTPBP2 may be a novel neurodegeneration with brain iron accumulation gene.

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Although Gtpbp2 is ubiquitously expressed, the phenotype in double mutants is confined to the nervous system, indicating that the brain-specific expression pattern of n-Tr20 may underlie the specificity of disease. Orthologues of GTPBP2 and n-Tr20 are present in humans, and a recent study linked a mutation in GTPBP2 to a family with cerebellar atrophy, retinal degeneration, and intellectual disability (Jaberi et al, 2016). While disruption of the ribosome recycling protein GTPBP2 causes devastating neurodegeneration in both humans and mouse, as of yet, there are no known neurological disorders associated with defects in canonical cytoplasmic translational termination.…”

Clinical delineation of GTPBP2‐associated neuro‐ectodermal syndrome: Report of two new families and review of the literature

“…Our patients are strikingly similar to those reported in Bertoli‐Avella et al with cerebellar hypoplasia, corpus callosum malformation, severe microcephaly, epilepsy, ectodermal manifestations, vision impairment, and dysmorphic features (Figures and , Appendix S1 and Table ). Interestingly, these patients all have nonsense mutations, while the three adult siblings reported in Jaberi et al have a milder neurological phenotype and splice site variants which may result in some functional protein. The nonsense variants in all other patients would probably trigger nonsense‐mediated decay leading to complete protein absence.…”

“…The first clinical report described three adult siblings with evidence of brain iron accumulation, while the three children (all under the age of 10 years) in the second report did not . However, the optimal technique for detecting brain iron is susceptibility‐weighted imaging (SWI), which was used in the first study but not in the second.…”

“…reported in Jaberi et al1 have a milder neurological phenotype and splice site variants which may result in some functional protein. The nonsense variants in all other patients would probably trigger nonsense-mediated decay leading to complete protein absence.…”

“…In 2016, Jaberi et al described a new syndrome caused by biallelic loss‐of‐function variants in the GTPBP2 gene. They reported a family of three adult siblings with a neurological disorder characterized by non‐progressive cognitive impairment, dystonia, ataxia, motor neuropathy, and retinal dysfunction.…”