Long mutant dystrophins and variable phenotypes: evasion of nonsense-mediated decay?

Kerr, Tim; Sewry, Caroline A.; Robb, Stephanie; Roberts, Roland G.

doi:10.1007/s004390100598

Cited by 113 publications

(95 citation statements)

References 23 publications

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“…The extent of the beneficial effect may vary depending on both the toxicity of truncated proteins encoded by different genes and the nature of traits. Rarely, as exemplified by the hemizygous X-linked DMD gene mutated in muscular dystrophy, NMD may result in more severe disease by abrogating the hypomorphic protein function 41 . Nevertheless, individuals potentially carry several silent PTCs in their genome and the suppression of these PTC-carrying alleles by NMD may be crucial for preventing disease expression, as implied by the embryonic lethality caused by congenital suppression of NMD in mice 42 .…”

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confidence: 99%

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

et al. 2004

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Different mutations in the same gene often cause distinct disease phenotypes in humans. Generally, such variations in the clinical phenotypes have been considered to be a consequence of the function or dysfunction of mutant proteins. Thus, a primary emphasis in genotype-phenotype correlation studies has been placed on determining the unique functional properties of encoded mutant proteins. But in vitro functional assays of mutant proteins often show discordance between predicted protein function and clinical outcome. Little is known about the many factors that are potentially involved in this discrepancy, but loss-of-function versus gain-of-function effects are often invoked as a possible mechanism.We previously identified two unrelated individuals with an unusual phenotype that combined four distinct syndromesperipheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease-that are characterized by deficiencies of Schwann cells, oligodendrocytes, melanocytes and enteric ganglia neurons, respectively 1,2 . Here we describe four more individuals and propose that this complex disorder is a newly described neurocristopathy called PCWH.We previously identified mutations in SOX10 in all affected individuals 1,2 . SOX10 is a transcription factor that contains a central high mobility group (HMG) DNA-binding domain and a transactivation domain at its C terminus 3 . SOX10 is essential for the development of cells in the neural crest lineage, including melanocytes and enteric ganglia neurons 4,5 ; it also controls the proliferation and differentiation of Schwann cells and oligodendrocytes [6][7][8] . Notably, some mutations in SOX10 also cause a distinct and more restricted disease that does not involve either the peripheral (PNS) or the central (CNS) nervous systems 9-11 . This less complicated neurocristopathy, called WS4, combines Waardenburg and Hirschsprung diseases 12 . Most SOX10 disease-associated mutations, regardless of whether they cause PCWH or WS4, result in premature termination codons (PTCs).As in SOX10, different mutations in MPZ are responsible for distinct neurological diseases, which each affect the myelin of the PNS. These neuropathies include early onset congenital hypomyelinating neuropathy (CHN; OMIM 605253), Dejerine-Sottas neuropathy (DSN; OMIM 145900) and the less severe, adult onset Charcot-MarieTooth disease type 1B (CMT1B; OMIM 118200; ref. 13). It has been suggested that the severity of alleles in CHN and DSN is due to dominant-negative effects, whereas the reduced severity of alleles in CMT1B is due to loss of function. But although some nonsense and frameshift alleles cause CMT1B, several truncating mutations have been reported that convey either a CHN or a DSN phenotype.We investigated the molecular mechanisms underlying the neurological phenotypes of the PCWH and WS4 neurocristopathies resulting from allelic SOX10 truncating mutations, as well as those underlying the CHN, DSN and CMT1B myelinopathies caused by allelic MPZ truncatin...

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confidence: 99%

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

et al. 2004

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“…Variability in the efficacy of NMD has been proposed as a possible explanation for the great phenotypic variability observed between patients harbouring truncating mutations 3 0 of exon 70 in the dystrophin gene. 32 Nonsense-mediated mRNA decay in mammalian cells generally occurs when a nonsense codon resides 450À55 nucleotides upstream of a splicing-generated exon -exon junction. On the basis of the current knowledge, the efficiency of NMD is generally not influenced by nonsense codon position, indicating that a higher number of downstream exon junction complex (EJC) of proteins does not lead to more efficient NMD.…”

Section: Point Mutations In Bmdmentioning

confidence: 99%

“…33 However, might a low number of EJCs induce a lower efficiency of NMD? Data of transcript and dystrophin analysis in a series of BMD patients carrying C-terminally truncating mutations would argue for this hypothesis, 32 and the low amount of dystrophin detected in patient D193 could be attributable to the reduced efficacy of NMD. In contrast with the BMD patient reported by Kerr et al 32 who carries the c. 10454delT mutation in exon 74 and presented with mental retardation, the truncated dystrophin in patient D193 allows rescue of both his muscle and cognitive phenotype.…”

Section: Point Mutations In Bmdmentioning

confidence: 99%

“…32,34 The dystrophin protein carries out its role in maintaining muscle fibres intact by binding via the N-terminal end to the subsarcolemmal cytoskeletal actin network, and via its cysteine-rich domain to b-dystroglycan. The above results suggest that the amino-acid residues 3471 -3500 are not essential for this role.…”

Section: Point Mutations In Bmdmentioning

confidence: 99%

“…36 Nevertheless, the absence of this region is compatible with a moderate phenotype in our patient as previously reported. 32,34 Many different strategies for DMD gene therapy have been studied and improved over the years. One promising development concerns the induction of exon-skipping events with small molecules that affect dystrophin gene splicing in order to restore the reading frame.…”

Section: Point Mutations In Bmdmentioning

confidence: 99%

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Mutation spectrum leading to an attenuated phenotype in dystrophinopathies

et al. 2005

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Although Becker muscular dystrophy (BMD; MIM 300376) is mainly caused by gross deletions of the dystrophin gene, the nature of the mutations involved in the remaining cases is of importance because of the milder clinical course of Becker. We have extensively characterized the mRNA changes associated with five novel point mutations giving rise to a Becker phenotype, which confirm that Becker arises largely due to alterations in splicing. In two cases the milder phenotype arises because of exon skipping, leading to an in-frame deletion (c.1603-2A4C and c.4250T4A). In further two cases intronic mutations (c.4519-5C4G and c.961-5925A4C) result in complex splicing changes, but with some residual normal transcripts. The last case, c.10412T4A (p.Leu3471X), results in a truncated transcript missing only part of the COOH terminal of the protein, suggesting that this region is not crucial for dystrophin function. The detection of a low amount of dystrophin in this patient could be attributable to a reduced efficiency of nonsensemediated decay. The results emphasize that mRNA analysis is important in defining Becker mutations and will be of value in assessing various gene therapy strategies.

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Inhibition of nonsense‐mediated mRNA decay rescues the phenotype in Ullrich's disease

Usuki

Yamashita

Higuchi

et al. 2004

Annals of Neurology

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Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance system that eliminates aberrant mRNAs containing premature translation termination codons (PTCs). We evaluated the role of NMD in of Ullrich's disease. The patient has a frameshift mutation with a PTC in the collagen VI alpha2 gene causing the loss of collagen VI and functional defects in extracellular matrix (ECM). The pharmacological block of NMD caused upregulation of the mutant collagen VI alpha2 subunit, resulting in collagen VI assembly and partially functional ECM formation. Our results suggest that NMD inhibitors can be used as a therapeutic tool to rescue some human genetic diseases exacerbated by NMD.

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Long mutant dystrophins and variable phenotypes: evasion of nonsense-mediated decay?

Cited by 113 publications

References 23 publications

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Mutation spectrum leading to an attenuated phenotype in dystrophinopathies

Inhibition of nonsense‐mediated mRNA decay rescues the phenotype in Ullrich's disease

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