This report describes neurodevelopmental disorder, GTPBP1/GTPBP2-related. Homozygous or biallelic mutations in GTPBP2 are associated with the disease Jaberi-Elahi syndrome (JABELS; MIM:61798800); while biallelic mutations in the paralogous human gene GTPBP1 result in a phenotypically identical syndromic neurodevelopmental disorder. There are two Drosophila orthologs to these genes, Dmel\Gtpbp1, a high-scoring ortholog of human GTPBP1 and moderate-scoring ortholog of GTPBP2; and Dmel\Gtpbp2, a high-scoring ortholog of GTPBP2 and moderate-scoring ortholog of GTPBP1. Classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both genes. Dmel\Gtpbp2 has been analysed in the context of human disease.
Neither human GTPBP1 nor GTPBP2 has been introduced into flies.
Homozygous or transheterozygous loss-of-function mutations of Dmel\Gtpbp2 result in reduced locomotor activity across a 24-hour day/night cycle in adult flies, as well a strong decrease in the magnitude of startle responses to lights-on and lights-off transitions. Pan-neuronal RNAi knockdown of Dmel\Gtpbp2 also results in reduction of peak locomotor responses to lights-on/lights-off transitions (FBrf0258488).
[updated Apr. 2024 by FlyBase; FBrf0222196]
The clinical syndrome associated with bi-allelic GTPBP1 or GTPBP2 variants can be defined as a complex syndromic neurodevelopmental disorder associated with severe neurodegeneration, epilepsy, choreiform movement disorder, and ectodermal abnormalities, with pathognomonic craniofacial features (Salpietro, et al, 2024, pubmed:38118446, FBrf0258488).
Jaberi-Elahi syndrome (JABELS) is an autosomal recessive neurodevelopmental disorder characterized by developmental delay and intellectual disability with additional variable features. Patients have onset of symptoms in infancy, but the severity is highly variable. Some patients have social interaction and learn to walk but have an ataxic gait and abnormal movements, such as tremor or dystonia, whereas others do not achieve any motor control and are unable to speak. Additional features may include retinal anomalies, visual impairment, microcephaly, abnormal foot or hand posturing, and kyphoscoliosis; some patients have dysmorphic facial features or seizures. Brain imaging typically shows cerebellar atrophy and hypoplasia of the corpus callosum (summary by Jaberi et al., 2016, pubmed:26675814, and Bertoli-Avella et al., 2018, pubmed: 29449720). [from MIM:617988; 2024.02.28]
Jaberi-Elahi syndrome (JABELS) is caused by homozygous or compound heterozygous mutation in the GTPBP2 gene on chromosome 6p21. [from MIM:617988; 2024.02.28
The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis (Zinoviev, et al., 2018, pubmed:30108131; Salpietro, et al, 2024, pubmed:38118446, FBrf0258488).
The GTPBP2 gene encodes a GTP-binding protein that is a member of the GTPase superfamily capable of binding GTP or GDP. G proteins are activated by binding GTP and are inactivated by hydrolyzing GTP to GDP. This general mechanism enables G proteins to perform a wide range of biologic activities (summary by Watanabe et al., 2000, pubmed:11054535 and Jaberi et al., 2016, pubmed:2667581). [from MIM:607434; 2024.02.28]
High-scoring ortholog of human GTPBP1, moderate-scoring ortholog of GTBP2 (2 Drosophila to 2 human).
High-scoring ortholog of human GTPBP2, moderate-scoring ortholog of GTBP1 (2 Drosophila to 2 human).
