Nonsense-mediated mRNA decayin health and disease

Frischmeyer, Pamela A.; Dietz, Harry C.

doi:10.1093/hmg/8.10.1893

Cited by 927 publications

(695 citation statements)

References 81 publications

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“…First, PTCs are common: nonsense and frameshift mutations are present in approximately one-third of mutations that cause human genetic disease 28,29 . Second, nonsense codons in all internal exons are capable of triggering NMD 23 , which means that mRNA levels will be reduced by most nonsense and frameshift mutations [28][29][30] ; therefore, PTCs generally result in milder phenotypes as compared with missense mutations, as has been postulated in several human diseases including osteogenesis imperfecta 31 , Stickler syndrome 32 and Marfan syndrome 33,34 . Third, on the basis that NMD has a potential role in most disease-causing PTCs, it has been proposed that haploinsufficiency is the most predictable pathogenetic mechanism underlying heterozygous nonsense alleles 29 .…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

et al. 2004

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“…It is important to note that no additional RNA band was detected using either probe, which showed the absence of additional hybrid RNA molecules that could produce hybrid proteins containing any portion of torsinA. Nonsense-mediated mRNA decay has been well documented in mammalian cells (Frischmeyer, 1999). Western blot analysis showed that homozygous Dyt1 STOP mice expressed approximately 36% less protein than the level expressed in WT mice ( Fig.…”

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confidence: 90%

Motor deficits and hyperactivity in Dyt1 knockdown mice

Dang

Yokoi²,

Pence³

et al. 2006

Neuroscience Research

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The DYT1 gene containing a trinucleotide deletion (ΔGAG) is linked to early-onset dystonia, a neurological movement disorder of involuntary muscle contractions. To understand Dyt1's contribution to dystonia, we produced and analyzed Dyt1 knockdown (KD) mice that expressed a reduced level of torsinA protein encoded by Dyt1. Knockdown mice exhibited deficits in motor control and a decreased trend in dopamine with a significant reduction in 3,4-dihydroxyphenylacetic acid. These alterations are similar to those displayed by previously reported Dyt1 ΔGAG knockin heterozygous mice, suggesting that the partial loss of torsinA function contributes to the pathology of the disease. KeywordsDyt1; torsinA; dystonia; knockdown; Tor1A; Dyt1 ΔGAG A trinucleotide deletion (ΔGAG) in the DYT1 gene is found in a majority of patients with Oppenheim's early-onset dystonia, a neurological disorder of uncontrollable muscle contractions (Ozelius et al., 1997). DYT1 codes for torsinA protein, and the ΔGAG deletion removes a glutamic acid (ΔE) from the protein. The role of mutant torsinA in the development of dystonia is unknown, but possible functions of normal torsinA were reported to include its involvement in cytoskeletal dynamics, nuclear membrane formation, and neuroprotection (Kuner et al., 2003;Bragg et al., 2004;Gonzalez-Alegre & Paulson, 2004;Goodchild & Dauer, 2004;Shashidharan et al., 2004;Hewett et al., 2006;Kock et al., 2006). Also unknown is the nature of the genetic mutation in torsinA, an important aspect of the pathophysiology of dystonia that may affect the development of genetic-based therapeutics.The ΔGAG mutation of DYT1 has been speculated to work through a toxic-gain-of-function mechanism by reports of protein aggregates caused by an overexpression of mutant torsinA in cultured cells and Drosophila (Hewett et al., 2000;Kustedjo et al., 2000;Koh et al., 2004). Also, in patient tissues and two mouse models, an overexpression transgenic and our Dyt1 ΔGAG knockin (Dyt1 ΔGAG) mouse lines, aggregates containing torsinA and ubiquitin were found primarily in the brainstem, even though torsinA is widely expressed throughout the brain Dang et al., 2005;Shashidharan et al., 2005). In contrast, other published findings have suggested that ΔGAG causes a loss of normal protein function (Torres et al., 2004;Goodchild et al., 2005). For example, nuclear envelope abnormalities were noted * To whom correspondence and proofs should be addressed. Yuqing Li, 3347 Beckman Institute, 405 N. Mathews Ave., Urbana, Illinois, 61801, Tel.:217-333-4002, Fax: 217-244-1726, E-mail: y-li4@uiuc.edu.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all l...

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“…Normal MLH1 expression, however, has also been described in tumours from subjects with small and large in-frame deletions and truncating mutations [51,55]. As the c.2252_2253delAA mutation is located in the last exon of MLH1, it is unlikely that the mutant mRNA is degraded by nonsense-mediated decay (NMD) [56]. Accordingly, Sanger sequencing of cDNA by 3 different carriers showed the balanced presence of both the wild-type and mutated transcripts (as shown in Online Resource 1).…”

Section: Discussionmentioning

confidence: 99%

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

et al. 2014

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The MLH1 c.2252_2253delAA mutation was\ud found in 11 unrelated families from a restricted area southwest\ud of Turin among 140 families with mutations in the\ud mismatch repair genes. The mutation is located in the highly\ud conserved C-terminal region, responsible for dimerization\ud with the PMS2 protein. Twenty-five tumour tissues from 61\ud individuals with the c.2252_2253delAA mutation were tested\ud for microsatellite instability(MSI) and protein expression.We\ud compared the clinical features of these families versus the rest\ud of our cohort and screened for a founder effect. All but one\ud tumours showed the MSI-high mutator phenotype. Normal,\ud focal and lack of MLH1 staining were observed in 16, 36 and\ud 48 % of tumours, respectively. PMS2 expression was always\ud lost. The mutation co-segregated with Lynch syndrome-related\ud cancers in all informative families. All families but one\ud fulfilled Amsterdam criteria, a frequency higher than in other\ud MLH1 mutants. This was even more evident for AC II (72.7\ud vs. 57.5 %). Moreover, all families had at least one colon\ud cancer diagnosed before 50 years and one case with multiple\ud Lynch syndrome-related tumours. Interestingly, a statistically\ud significant (p = 0.0057) higher frequency of pancreatic\ud tumourswas observed compared to familieswith other MLH1\ud mutations: 8.2 % of affected individuals versus 1.6 %. Haplotype\ud analysis demonstrated a common ancestral origin of the\ud mutation, which originated about 1,550 years ago. The\ud mutation is currently classified as having an uncertain clinical\ud significance. Clinical features, tissue analysis and co-segregation\ud with disease strongly support the hypothesis that the\ud MLH1 c.2252_2253delAA mutation has a pathogenic effec

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Nonsense-mediated mRNA decayin health and disease

Cited by 927 publications

References 81 publications

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

Motor deficits and hyperactivity in Dyt1 knockdown mice

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

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