Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonsense-mediated mRNA decay (NMD) is of universal biological significance. It has emerged as an important global RNA, DNA and translation regulatory pathway. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype and one with the FG phenotype. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.
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PMID:Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. 1770 78

Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.
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PMID:Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism. 1923 51

X-linked intellectual disability (XLID) is known to explain up to 10% of the intellectual disability in males. A large number of families in which intellectual disability is the only clinically consistent manifestation have been described. While linkage analysis and candidate gene testing were the initial approaches to find genes and variants, next generation sequencing (NGS) has accelerated the discovery of more and more XLID genes. Using NGS, we resolved the genetic cause of MRX82 (OMIM number 300518), a large Spanish Basque family with five affected males with intellectual disability and a wide phenotypic variability among them despite having the same pathogenic variant. Although the previous linkage study had mapped the locus to an interval of 7.6Mb in Xq24-Xq25 of the X chromosome, this region contained too many candidate genes to be analysed using conventional approaches. NGS revealed a novel nonsense variant: c.118C > T; p.Gln40* in UPF3B, a gene previously implicated in XLID that encodes a protein involved in nonsense-mediated mRNA decay (NMD). Further molecular studies showed that the mRNA transcript was not completely degraded by NMD. However, UPF3B protein was not detected by conventional Western Blot analysis at least downstream of the 40 residue demonstrating that the phenotype could be due to the loss of functional protein. This is the first report of a premature termination codon before the three functional domains of the UPF3B protein and these results directly implicate the absence of these domains with XLID, autism and some dysmorphic features.
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PMID:Molecular and Clinical Characterization of a Novel Nonsense Variant in Exon 1 of the UPF3B Gene Found in a Large Spanish Basque Family (MRX82). 3173 52