Novel mutations involving the NF1 gene coding sequence in neurofibromatosis type 1 patients from Taiwan

Liu, Ming-Tzen; Su, J.; Huang, Chunyu; Tsai, Shih‐Feng

doi:10.1007/s10038-003-0066-7

Cited by 5 publications

(2 citation statements)

References 7 publications

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“…To date, only a few NF1 mutations have been reported in patients with a Chinese background [Liu et al, 2003;Cai et al, 2005]. The present study represents the first large cohort genetic study of Neurofibromatosis type 1 patients from Taiwan of Chinese origin.…”

Section: Discussionmentioning

confidence: 89%

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: 89%

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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“…No other patient with precisely the same mutation seen in the present case has been described in the literature, although a mutation involving NF1 exon 13 was reported in a Taiwanese patient. He had a deletion that ''resulted in skipping of exon 13 … causing the loss of the GAPrelated domain [Liu et al, 2003].…”

Section: Nf1 Mutationmentioning

confidence: 99%

Ketotifen suppression of NF1 neurofibroma growth over 30 years

Riccardi¹

2015

American J of Med Genetics Pt A

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A patient with NF1 was treated with oral ketotifen for 30 years since infancy. Review of the patient's course and treatment details establishes a basis for reconsideration of several fundamental precepts about NF1 pathogenesis. The data suggest a distinctive benefit to treating an NF1 patient with an inhibitor of mast cell degranulation before cutaneous neurofibromas are clinically apparent: the neurofibromas appear to be arrested at a very early stage of development. The patient's skin was especially remarkable for both the paucity of cutaneous neurofibromas and the distinctive monotonous uniformity of those present, which were small and flat or barely sessile. While the data do not, of themselves, prove that ketotifen treatment commencing in childhood preempts neurofibroma maturation, in the context of earlier publications, they certainly warrant further investigation.

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Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele

et al. 2008

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Neurofibromatosis type 1 (NF1) is a common genetic disease caused by haploinsufficiency of the NF1 tumor-suppressor gene. Different pathogenetic mechanisms have been identified, with the majority (95%) causing intragenic lesions. Single or multiexon NF1 copy number changes occur in about 2% of patients, but little is known about the molecular mechanisms behind these intragenic deletions. We report here on the molecular characterization of a novel NF1 multiexonic deletion. The application of a multidisciplinary approach including multiplex ligation-dependent probe amplification, allelic segregation analysis, and fluorescent in situ hybridization allowed us to map the breakpoints in IVS27b and IVS48. Furthermore, the breakpoint junction was characterized by sequencing. Using bioinformatic analysis, we identified some recombinogenic motifs in close proximity to the centromeric and telomeric breakpoints and predicted the presence of a mutated messenger ribonucleic acid, which was deleted between exons 28 and 48 and encodes a neurofibromin that lacks some domains essential for its function. Through reverse transcriptase-polymerase chain reaction, the expression of the mutated allele was verified, showing the junction between exons 27b and 49 and, as expected, was not subjected to nonsense-mediated decay. Multiexonic deletions represent 2% of NF1 mutations, and until now, the breakpoint has been identified in only a few cases. The fine characterization of multiexonic deletions broadens the mutational repertoire of the NF1 gene, allowing for the identification of different pathogenetic mechanisms causing NF1.

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Novel mutations involving the NF1 gene coding sequence in neurofibromatosis type 1 patients from Taiwan

Cited by 5 publications

References 7 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

Ketotifen suppression of NF1 neurofibroma growth over 30 years

Breakpoint characterization of a novel NF1 multiexonic deletion: a case showing expression of the mutated allele

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