An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in Exon 17 of the NF1 gene (c.2970-2972 delAAT):: evidence of a clinically significant NF1 genotype-phenotype correlation

被引:252
作者
Upadhyaya, M.
Huson, S. M.
Davies, M.
Thomas, N.
Chuzhanova, N.
Giovannini, S.
Evans, D. G.
Howard, E.
Kerr, B.
Griffiths, S.
Consoli, C.
Side, L.
Adams, D.
Pierpont, M.
Hachen, R.
Barnicoat, A.
Li, H.
Wallace, P.
Van Biervliet, J. P.
Stevenson, D.
Viskochil, D.
Baralle, D.
Haan, E.
Riccardi, V.
Turnpenny, P.
Lazaro, C.
Messiaen, L.
机构
[1] Cardiff Univ, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales
[2] St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England
[3] St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England
[4] John Radcliffe Hosp, Dept Clin Genet, Oxford OX3 9DU, England
[5] Albany Med Ctr, Albany, NY USA
[6] Childrens Hosp & Clin, Minneapolis, MN USA
[7] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA
[8] Univ London, Inst Child Hlth, London WC1N 1EH, England
[9] Univ Florida, Gainesville, FL 32611 USA
[10] Acad Hosp St Jan, Brugge, Belgium
[11] Univ Utah, Div Med Genet, Salt Lake City, UT USA
[12] Addenbrookes Hosp, Dept Med Genet, Cambridge, England
[13] Univ Adelaide, Dept Paediat, Adelaide, SA, Australia
[14] Womens & Childrens Hosp, Dept Med Genet, Adelaide, SA, Australia
[15] Neurofibromatosis Inst, Crescenta, Italy
[16] Royal Devon & Exeter Hosp, Exeter EX2 5DW, Devon, England
[17] Inst Catala Oncol, Barcelona, Spain
[18] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA
关键词
D O I
10.1086/510781
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (! 20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 ( 14 familial and 7 sporadic cases) who were all found to have the same c. 2970-2972 delAAT(p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c. 2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) (Delta Met991), in conjunction with silent ACA -> ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.
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页码:140 / 151
页数:12
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