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Title: Mutational analysis of patients with neurofibromatosis 2

Abstract

Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous-system tumors in young adulthood. The NF2 gene has recently been isolated and found to encode a new member, merlin, of the protein 4.1 family of cytoskeleton-associated proteins. To define the molecular basis of NF2 in affected individuals, the authors have used SSCP analysis to scan the exons of the NF2 gene from 33 unrelated patients with NF2. Twenty unique SSCP variants were seen in 21 patients; 10 of these individuals were known to be the only affected person in their kindred, while 7 had at least one other known affected relative. In all cases in which family members were available, the SSCP variant segregated with the disease; comparison of sporadic cases with their parents confirmed the de novo variants. DNA sequence analysis revealed that 19 of the 20 variants observed are predicted to lead to a truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing. A single patient carried a 3-bp deletion removing a phenylalanine residue. The authors conclude that the majority of NF2 patients carry an inactivating mutation of the NF2 gene and that neutral polymorphism in themore » gene is rare. 18 refs., 3 figs., 2 tabs.« less

Authors:
; ; ; ; ; ; ; ; ;  [1]
  1. (and others)
Publication Date:
OSTI Identifier:
6872363
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Human Genetics; (United States); Journal Volume: 55:2
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ANIMAL CELLS; SKELETON; NERVOUS SYSTEM; NEOPLASMS; DNA SEQUENCING; GENE MUTATIONS; BODY; DISEASES; MUTATIONS; ORGANS; STRUCTURAL CHEMICAL ANALYSIS 550400* -- Genetics

Citation Formats

MacCollin, M., Ramesh, V., Pulaski, K., Trofatter, J.A., Short, M.P., Bove, C., Jacoby, L.B., Louis, D.N., Rubio, M.P., and Eldridge, R. Mutational analysis of patients with neurofibromatosis 2. United States: N. p., 1994. Web.
MacCollin, M., Ramesh, V., Pulaski, K., Trofatter, J.A., Short, M.P., Bove, C., Jacoby, L.B., Louis, D.N., Rubio, M.P., & Eldridge, R. Mutational analysis of patients with neurofibromatosis 2. United States.
MacCollin, M., Ramesh, V., Pulaski, K., Trofatter, J.A., Short, M.P., Bove, C., Jacoby, L.B., Louis, D.N., Rubio, M.P., and Eldridge, R. 1994. "Mutational analysis of patients with neurofibromatosis 2". United States. doi:.
@article{osti_6872363,
title = {Mutational analysis of patients with neurofibromatosis 2},
author = {MacCollin, M. and Ramesh, V. and Pulaski, K. and Trofatter, J.A. and Short, M.P. and Bove, C. and Jacoby, L.B. and Louis, D.N. and Rubio, M.P. and Eldridge, R.},
abstractNote = {Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous-system tumors in young adulthood. The NF2 gene has recently been isolated and found to encode a new member, merlin, of the protein 4.1 family of cytoskeleton-associated proteins. To define the molecular basis of NF2 in affected individuals, the authors have used SSCP analysis to scan the exons of the NF2 gene from 33 unrelated patients with NF2. Twenty unique SSCP variants were seen in 21 patients; 10 of these individuals were known to be the only affected person in their kindred, while 7 had at least one other known affected relative. In all cases in which family members were available, the SSCP variant segregated with the disease; comparison of sporadic cases with their parents confirmed the de novo variants. DNA sequence analysis revealed that 19 of the 20 variants observed are predicted to lead to a truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing. A single patient carried a 3-bp deletion removing a phenylalanine residue. The authors conclude that the majority of NF2 patients carry an inactivating mutation of the NF2 gene and that neutral polymorphism in the gene is rare. 18 refs., 3 figs., 2 tabs.},
doi = {},
journal = {American Journal of Human Genetics; (United States)},
number = ,
volume = 55:2,
place = {United States},
year = 1994,
month = 8
}
  • Samples of constitutional DNA from 60 unrelated patients with adenomatous polyposis coli (APC) were examined for mutations in the APC gene. Five inactivating mutations were observed among 12 individuals with APC; all were different from the six inactivating mutations previously reported in this panel of patients. The newly discovered mutations included single-nucleotide substitutions leading to stop codons and small deletions leading to frameshifts. Two of the mutations were observed in multiple APC families and in sporadic cases of APC; allele-specific PCR primers were designed for detecting mutations at these common sites. No missense mutations that segregated with the disease weremore » found. 28 refs., 5 figs., 1 tab.« less
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  • Familial hyperekplexia or Startle disease (STHE) is a rare autosomal dominant neurologic disorder manifested by marked muscular hypertonia in infants and exaggerated startle response that persists throughout the lifetime of the patient. This disorder is caused by mutations in the {alpha}{sub 1} subunit of the receptor for the inhibitory neurotransmitter glycine (GLRA1). Previously, we have reported three mutations, two of which change arginine 271 (Arg 271) to uncharged amino acids and a third which changes a tyrosine at amino acid 279 to a cysteine. The most common mutation, detected in three of six original families, is a G to Amore » transition mutation at Arg 271. Four new STHE patients have been screened and were found to have the most common Arg 271 mutation. Three of the new patients have a clear family history while family information on the fourth patient was unavailable. Four possible sporadic cases of STHE have been screened by DGGE in all exons of the GLRA1 gene and no mutations have been detected. These sporadic cases may represent defects from other causes. A new three-allele dinucleotide repeat polymorphism at the GLRA1 locus has been detected. Haplotype analysis of two polymorphisms at the GLRA1 locus and CA-repeat polymorphism, D5S119, suggests that the most common mutation arose at least two and most likely three independent times. Thus, it appears that at least five independent GLRA1 mutation events (two of which are identical) have occurred in ten STHE families. The fact that these mutations affect only two amino acids suggests that the dominant STHE phenotype can only be caused by abnormalities in a highly restricted region of GLRA1.« less
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  • We explored the mitochondrial 12S rRNA and the tRNA{sup Ser(UCN)} genes in 100 Tunisian families affected with NSHL and in 100 control individuals. We identified the mitochondrial A1555G mutation in one out of these 100 families and not in the 100 control individuals. Members of this family harbouring the A1555G mutation showed phenotypic heterogeneity which could be explained by an eventual nuclear-mitochondrial interaction. So, we have screened three nuclear genes: GJB2, GJB3, and GJB6 but we have not found correlation between the phenotypic heterogeneity and variants detected in these genes. We explored also the entire mitochondrial 12S rRNA and themore » tRNA{sup Ser(UCN)} genes. We detected five novel polymorphisms: T742C, T794A, A813G, C868T, and C954T, and 12 known polymorphisms in the mitochondrial 12S rRNA gene. None of the 100 families or the 100 controls were found to carry mutations in the tRNA{sup Ser(UCN)} gene. We report here First mutational screening of the mitochondrial 12S rRNA and the tRNA{sup Ser(UCN)} genes in the Tunisian population which describes the second family harbouring the A1555G mutation in Africa and reveals novel polymorphisms in the mitochondrial 12S rRNA gene.« less