Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease

Khajavi, Mehrdad; Inoue, Ken; Lupski, James R.

doi:10.1038/sj.ejhg.5201649

Cited by 361 publications

(328 citation statements)

References 60 publications

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“…For example, the efficiency of the NMD pathway can alter the pattern of inheritance in several genetic disorders. 11 We report here the characterization of a recessive inheritance of EDS linked to a COL3A1 null allele, inherited by descent in a consanguineous child. Recessive inheritance of EDS type IV has been suggested in the past.…”

Section: Discussionmentioning

confidence: 99%

Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome

et al. 2009

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So far, mutations in the human COL3A1 gene have been associated with the predominantly inherited Ehlers-Danlos syndrome (EDS), vascular type. Genotype -phenotype correlation perspectives collapsed, as haploinsufficiency, which was long suggested to confer a milder or unrecognized phenotype, was reported in four patients with a phenotype similar to that of vascular EDS. Here, we study a case of recessive EDS in a young consanguineous girl of healthy parents. She fulfilled the vascular EDS criteria for laboratory testing. Total sequencing of COL3A1 cDNA identified a homozygous nucleotide duplication (c.479dupT) resulting in a premature termination codon (p.Lys161GlnfsX45). Studies in genomic DNA showed that this mutation was inherited from each parent. The expression analysis (RT-PCR, quantitative-PCR, immunohistochemistry, WB) showed strong mRNA decay and an absence of type III collagen in the proband. The expected COL3A1 haploinsufficiency in her healthy ascendants did not lead to the manifestations of vascular EDS. This case provides evidence of a stochastic effect of COL3A1 haploinsufficiency in humans, which could be explained by the relation between nonsense-mediated mRNA decay efficiency and the resulting dominant-negative effect depending on the position of the mutation and/or modifying factors. It opens up new perspectives for the understanding of COL3A1 genotype -phenotype correlations, which is required while considering targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome

et al. 2009

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“…This pathway of mRNA surveillance degrades transcripts containing premature termination codons. 10 Therefore, the phenotype of the patient is probably dependent on the dysfunction of the ALADIN L430F only. Intriguingly, functional testing of the novel p.Leu430Phe mutation revealed a correct localization of GFP -ALADIN L430F at the NPC.…”

Section: Discussionmentioning

confidence: 99%

Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe

et al. 2008

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The triple A syndrome is caused by autosomal recessively inherited mutations in the AAAS gene and is characterized by achalasia, alacrima and adrenal insufficiency as well as progressive neurological impairment. We report on a 14-year-old girl with slowly progressive axonal motor neuropathy with conspicuous muscle wasting of hypothenars and calves as well as alacrima. The mutation analysis of the AAAS gene revealed a compound heterozygous mutation: a c.251G4A mutation in exon 2 that had been reported previously, and a novel c.1288C4T mutation in exon 14. At the transcriptional level, the c.251G4A transition results in an aberrant splicing and decay of this RNA strand so that the particular clinical picture results from the novel c.1288C4T, (p.Leu430Phe, L430F) mutation in a hemizygous form.With transfection experiments, we demonstrate that GFP -ALADIN L430F correctly localizes to nuclear pore complexes. Therefore, we conclude that this point mutation impairs ALADIN function at the nuclear pore.

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“…Therefore, it is logical to assume that the CC or CT genotype of the 3Ј-UTR of the HLA-E gene polymorphism may affect serum/plasma levels of soluble HLA-E or the development of CAA in KD patients, although the influence of this SNP on the production of soluble HLA-E by vascular endothelial cells remains unknown. A possible explanation for the influence of the 3Ј-UTR may be because specific sequences in the 3Ј-UTR of RNA, together with stabilizing and destabilizing proteins, determine the messenger RNA stability and, consequently, the level of expression of proteins (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

HLA–E gene polymorphism associated with susceptibility to kawasaki disease and formation of coronary artery aneurysms

Lin¹,

Wan²,

Wu³

et al. 2009

Arthritis & Rheumatism

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Objective. Kawasaki disease (KD) is a pediatric systemic vasculitis of unknown cause for which a genetic influence is supposed. The purpose of this study was to identify possible genetic variants in the major histocompatibility complex (MHC) region that are associated with KD and the development of coronary artery aneurysms (CAAs) in a Taiwanese population.Methods. The 168 genetic variants covering the MHC locus were analyzed in an association study of a Taiwanese cohort of 93 KD patients and 680 unrelated healthy children matched for sex and age with the study patients.Results. Eleven single-nucleotide polymorphisms (SNPs) were associated with the occurrence of KD. The SNP located at the 3 -untranslated region of HLA-E (rs2844724) was highly associated (P < 1 ؋ 10 ؊7 ). In addition, the frequency of the C allele was higher in KD patients without CAAs than in controls (P < 0.001) due to a significantly increased frequency of the CC and CT genotypes. Plasma levels of soluble HLA-E were significantly higher in KD patients than in controls regardless of the presence of CAAs. Furthermore, there was a trend toward higher plasma levels of soluble HLA-E in KD patients with the CT and TT genotypes of the HLA-E gene polymorphism.Conclusion. Our results suggest that the HLA-E gene polymorphism may play a role in the pathogenesis of KD.

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Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease

Cited by 361 publications

References 60 publications

Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome

Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome

Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe

HLA–E gene polymorphism associated with susceptibility to kawasaki disease and formation of coronary artery aneurysms

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