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

Abstract

The GTPBP2 gene encodes a guanosine triphosphate (GTP)‐binding protein of unknown function. Biallelic loss‐of‐function variants in the GTPBP2 gene have been previously reported in association with a neuro‐ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age‐related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

“…This conclusion is supported by a genome-wide association analysis which included NEMF variants among several genes potentially implicated in cognitive phenotypes 21 . Similarly, mutation of GTPBP2, a GTPase that mediates the splitting of stalled ribosomes upstream of RQC 22 , causes Jaberi-Elahi syndrome [23][24][25] , an early onset neurodegenerative disease characterized by dystonia, motor and sensory neuropathy, ataxia, and cognitive dysfunction. Future experiments will address the potential for cognitive dysfunction in Nemf mutant mice, although we anticipate that the interpretation of such analyses may be confounded by the presence of motor and sensory deficits.…”

Cerebral Iron Deposition in Neurodegeneration

“…Other rare genetic disorders were suggested to belong to the NBIA group, mostly based on brain MRI findings, i.e., decreased basal ganglia signal on T2/T2* or susceptibility weighted images (reviewed in [239]): Fatty acid 2 hydroxylase-associated neurodegeneration [240], Woodhouse-Sakati syndrome caused by mutations in DCAF17 gene [241,242], Kufor-Rakeb syndrome caused by ATP13A2 mutations [243,244], Adaptor protein complex 4 (AP4) deficiency [245], sterol carrier protein 2 (SCP2) deficiency [246], DDHD1 encoding phospholipase A1 [247], FBXO7 deficiency [248], GTP-binding protein 2 (GTPBP2) deficiency [249,250], fucosidosis [251], GM1 gangliosidosis [252], VAC14 syndrome [253], and TBCE [254], KMT2B [255], IRF2BPL [256], REPS1, and CRAT mutations [182]. Further research into brain Fe homeostasis in these disorders may generate important information regarding mechanisms and consequences of brain Fe disturbances.…”

The trinity of ribosome-associated quality control and stress signaling for proteostasis and neuronal physiology

“…The CNS-specific tRNA deficiency in Gtpbp1 mutant mice also causes ribosomal stalling, ISR activation, and neurodegeneration, indicating the non-redundant role of these two ribosome-rescue factors (i.e., GTPBP1 and GTPBP2) (88). Not surprisingly, mutant alleles in human GTPBP2 have been shown to associate with Jaberi-Elahi syndrome, and the affected individuals manifest prenatal onset neurological dysfunction with an age-dependent accumulation of brain iron (89)(90)(91). Pathogenic HBS1L variants also associate with multiple congenital anomalies, including microcephaly and general developmental delay (92,93).…”