Characterisation of inherited and sporadic mutations in neurofibromatosis type-1

Sm, Purandare; Wg, Lanyon; Jm, Connor

doi:10.1093/hmg/3.7.1109

Cited by 47 publications

(21 citation statements)

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“…Approximately two-thirds of the mutations (43/63) are predicted to cause premature termination of the peptide sequence, which is also consistent with previous data. Fifteen mutations observed in the present cohort have also been reported in other populations [Purandare et al, 1994;Heim et al, 1995;Park and Pivnick, 1998;Fahsold et al, 2000;Messiaen et al, 2000;Toliat et al, 2000]. Whether they have a common ancestor or constitute de novo repeat mutations will require additional studies to resolve.…”

Section: Discussionmentioning

confidence: 56%

Identification of forty-five novel and twenty-three knownNF1 mutations in Chinese patients with neurofibromatosis type 1

Lee

You

et al. 2006

Hum. Mutat.

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Neurofibromatosis type 1 (NF1), characterized by skin neurofibromas and an excess of café-au-lait spots, is due to mutations in the neurofibromin (NF1) gene. Identifying the genetic defect in individuals with the disease represents a significant challenge because the gene is extremely large with a high incidence of sporadic mutations across the entire gene ranging from single nucleotide substitutes to large deletions. In the present study, we have used a combination of techniques (heteroduplex analysis, sequencing, loss of heterozygosity and quantification of gene dosage) to define the genetic defect in 68 individuals from a cohort of 107 NF1 Taiwanese patients of Chinese origin. Fifty-eight were initially identified using heteroduplex analytical techniques and confirmed by sequence analysis. A further five were identified by direct sequence analysis alone. The reminders were shown to carry large deletions in the NF1 gene by demonstrating loss of heterozygosity that was confirmed by gene dosage measurements using quantitative-PCR techniques. Mis-sense, non-sense, frameshift or splice-site mutations were identified across the entire gene of which the majority (45/68) were novel in nature. The detection rate with the various analytical techniques and the types of mutation detected are consistent with published data involving both individuals and large cohort studies from other ethnic backgrounds. INTRODUCTIONWith a frequency of 1/3000 live births, Neurofibromatosis type 1 (NF1; MIM# 162200) is one of the most common autosomal dominant disorders involving the human nervous system [Friedman, 1999]. The clinical features of the disease include: café-au-lait spots, cutaneous or subcutaneous neurofibromas, large plexiform neurofibromas, Lisch nodules and skin freckling. Other features such as scoliosis, macrocephaly, pseudoarthrosis, short stature, mental sub-normality and malignancies are present in a minority of patients 1997]. Except for the discoloration of the skin (Café-au-lait macules), which can be identified at a very young age, most of the other clinical features usually occur insidiously after puberty.The NF1 gene (NM_000267.1), which spans approximately 350Kb of genomic sequence on chromosome 17q11.2, is composed of 60 exons coding an 8.9Kb mRNA [Cawthon et al., 1990a;Wallace et al., 1990]. NF1 gene product, neurofibromin, is a 250 KDa hydrophilic protein comprising 2818 amino acids [Cawthon et al., 1990b]. The central region of neurofibromin displays marked homology with Ras-GTPase activation proteins (GAPs) that are involved in the negative regulation of RAS-mediated signal transduction pathways [Cichowski and Jacks, 2001].The mutation rate at the NF1 gene is estimated to be ~1x10 -4 /gamete/generation making it one of the highest of any human disease genes [Huson et al., 1989;Upadhyaya and Cooper, 1998]. Mutations encompass both single nucleotide substitutions and large genomic deletions [Stenson et al., 2003]. Approximately a half of all mutations arise de novo and do not appear to be clustered within...

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Section: Discussionmentioning

confidence: 56%

Identification of forty-five novel and twenty-three knownNF1 mutations in Chinese patients with neurofibromatosis type 1

Lee

You

et al. 2006

Hum. Mutat.

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“…The predominant effect of Y2264X (TAC to TAA or to TAG) on mRNA is the skipping of exon 37, an observation not yet reported for other nonsense mutations in the NF1 gene (Horiuchi et al 1994;Purandare et al 1994;Valero et al 1994;Heim et al 1995;Legius et al 1995;Robinson et al 1995;Gasparini et al 1996;Horn et al 1996;Upadhyaya et al 1996). Alteration of splice site selection in vivo is an only recently documented consequence of some nonsense mutations.…”

Section: Discussionmentioning

confidence: 96%

Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene

et al. 1997

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Neurofibromatosis type 1 (NF1), characterised by peripheral neurofibromas, café-au-lait spots and iris Lisch nodules, is one of the most common inherited disorders. We have analysed exons 35 to 49 in 21 unrelated NF1 patients using reverse transcription-polymerase chain reaction and protein truncation analysis. In two unrelated patients we found skipping of exon 37 at the cDNA level. Sequence analysis of genomic DNA revealed the presence of a C6792A transversion in one patient and a C6792G transversion in a second patient; both transversions change the codon for tyrosine to a nonsense codon. Sequencing of the exonic sequences as well as the branch sites, and the 3' and 5' splice sites of exons 36, 37 and 38 did not reveal any additional sequence abnormality. This is the first report showing that nonsense mutations in the NF1 gene can induce the skipping of a constitutive exon.

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“…The significance of region II in the interaction with Ras is further supported by site-directed mutagenesis studies (11) as well as by the identification of NF1 patient mutations at residues 1391 (34a), 1419 (27), and 1423 (17). These mutations affect Ras interaction and/or GAP activity (15a, 17, 24).…”

Section: Discussionmentioning

confidence: 99%

“…The K1423E (Lys-14233Glu) mutation found in samples from NF1 patients (17) results in a more than 125-fold decrease in the interaction with Ras proteins and a dramatic decrease in GAP activity (24). Recently, an additional GRD mutation, K1419R, which is located near K-1423, has been isolated from patients (27). The importance of conserved residues has been demonstrated by site-directed mutagenesis of NF1-GRD (11).…”

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confidence: 99%

Identification of Neurofibromin Mutants That Exhibit Allele Specificity or Increased Ras Affinity Resulting in Suppression of Activated ras Alleles

Morcos

Thapar

Tusneem

et al. 1996

Molecular and Cellular Biology

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Neurofibromin plays a critical role in the downregulation of Ras proteins in neurons and Schwann cells. Thus, the ability of neurofibromin to interact with Ras is crucial for its function, as mutations in NF1 that abolish this interaction fail to maintain function. To investigate the neurofibromin-Ras interaction in a systematic manner, we have carried out a yeast two-hybrid screen using a mutant of H-ras, H-ras D92K, defective for interaction with the GTPase-activated protein-related domain (GRD) of NF1. Two screens of a randomly mutagenized NF1-GRD library led to the identification of seven novel NF1 mutants. Characterization of the NF1-GRD mutants revealed that one class of mutants are allele specific for H-ras D92K. These mutants exhibit increased affinity for H-ras D92K and significantly reduced affinity for wild-type H-ras protein. Furthermore, they do not interact with another H-ras mutant defective for interaction with GTPase-activating proteins. Another class of mutants are high-affinity mutants which exhibit dramatically increased affinity for both wildtype and mutant forms of Ras. They also exhibit a striking ability to suppress the heat shock sensitive traits of activated RAS2 G19V in yeast cells. Five mutations cluster within a region encompassing residues 1391 to 1436 (region II). Three NF1 patient mutations have previously been identified in this region. Two mutations that we identified occur in a region encompassing residues 1262 to 1276 (region I). Combining high-affinity mutations from both regions results in even greater affinity for Ras. These results demonstrate that two distinct regions of NF1-GRD are involved in the Ras interaction and that single amino acid changes can affect NF1's affinity for Ras.

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Characterisation of inherited and sporadic mutations in neurofibromatosis type-1

Cited by 47 publications

References 0 publications

Identification of forty-five novel and twenty-three knownNF1 mutations in Chinese patients with neurofibromatosis type 1

Identification of forty-five novel and twenty-three knownNF1 mutations in Chinese patients with neurofibromatosis type 1

Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene

Identification of Neurofibromin Mutants That Exhibit Allele Specificity or Increased Ras Affinity Resulting in Suppression of Activated ras Alleles

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