UDP_755 patient presents craniosynostosis, microcephaly, congenital extremity contractures, and global developmental delay. Genomic sequencing and bioinformatics analyses by the NIH-UDP program have identified two mutant variants, GBAS (NM_001483.2: c.181C>G; p.His61Asp) and SLC41A2 (NM_032148.3: c.1648G>A; p.Gly550Arg) as candidate causal mutations for UDP_755. GBAS gene encodes glioblastoma amplified sequence, a member of the NIPSNAP (4-nitrophenylphosphatase domain and non-neuronal SNAP25-like) gene family. GBAS is also known as NIPSNAP2. SLC41A2 encodes solute carrier family 41, member 2. SLC41A2 has been reported to mediate voltage-dependent Mg2+ uptake activity when expressed in Xenopus oocytes. The function of GBAS and SLC41A2 are largely unknown and no previous mutations have been identified or characterized. We plan to study the function of GBAS and SLC41A2 in vivo and establish Drosophila models for UDP_755, in collaboration with UDP to investigate the underlying genetics, biochemistry and pathophysiology of the GBAS and SLC41A2 mutant variants. The goal of this proposal is to seek mechanistic understanding of (1) the nature of mutant variant of GBAS and SLC41A2 identified in UDP_755, (2) the normal function of GBAS and SLC41A2, specifically in the nervous system, (3) the genetic interaction of GBAS and SLC41A2 in vivo, and (4) the pathological consequence of the combination of GBAS and SLC41A2 mutant alleles. Our studies proposed here will characterize the neuronal function of GBAS and SLC41A2 and analyze the neurological phenotypes associated with human mutant variants. The result will provide significant and important insights into the function of GBAS and SLC41A2 and the disease pathophysiology associated with UDP_755 neurological disorder. We believe that our multidisciplinary approaches involving several research models are the most appropriate to accelerate discoveries that can be subsequently translated to humans.
In the NIH-UDP program, two mutant variants, GBAS (NM_001483.2: c.181C>G; p.His61Asp) and SLC41A2 (NM_032148.3: c.1648G>A; p.Gly550Arg) were identified in one patient, UDP_755 with craniosynostosis, microcephaly, and global developmental delay. We plan to study the individual function of GBAS and SLC41A2 in the nervous system using Drosophila genetic models, and analyze the neurological phenotypes associated with human mutant variants in collaboration with UDP. The result will provide significant and important insights into the function of GBAS and SLC41A2 and the disease pathophysiology associated with UDP_755 neurological disorder.
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