Neurofibromatosis type 1 (NF 1 ) is one of dm most common autosomal dominant conditions in humans ( 1 in 3000) ( 1 ) and one of the most important inheritable disorders of the nervous system in children. It is characterized by several developmental abnormalities involving tissues of neural crest origin, including an increased incidence of benign and malignant tumors (2) . The NF 1 gene has been ísolated (3 , 4, 5) and has been found to encode an ubiquitous protein, known as neurofibromin (6) . This protein displays a region of homology to human p l20gap , the p2 1 ras GTPase activatíng protein (GAP) (7) . When expressed in non mammalian systems , the GAP-related domain (NF 1 GRD) of the NF 1 gene produces a protein with GAP-like activity which stimulates the intrinsic GTPase actîvity of normal p2 l ras (8) and complements the loss of IRA 1 and IRA2 function in yeast (9) . It has been reeenfly demonstrated that in Schwann eells , neurofibmmín acts as an upstream negative regulator of the proto oncogene ras21 product, strongly supporting the hypothesis that the NF 1 gene is a tumor-suppressor gene ( 10 , 1 1 ) . The characterization of mutauons in the NF 1 gene s]hould also provide clues for the understanding of the molecular basis of the disease and the function of neurofibromin . To date only a few mutatìons of the NE I gene have been described (3 - 5 , 12 - 20). Despíte the large s e of the gene , 1 3 to 1 5 Kb cDNA (2 1 ) , and the high frequency of spontaneous mutations ( 1 × 10 -4/gamete/ generation) ( 1 ) , large and medium size rearrangements are infrequent . This leads to the necessity to screen all the coding sequence , analyzing every single exon of the gene and the intron -exon boundaries , looking for subtle rearrangements and trying to detect regions that might be higly susceptible to mutations. We describe here the molecular study of the NF 1 gene that has been conducted on a sample of 54 NF 1 affected individuals and the identification of a frameshift mutation that has occured in the FLR exon, one of the most conserved parts of the .-NF 1 catalytic domain (NF 1 GRD) ( 1 7).

A new disease-causing mutation in the GAP-related domain of the NF1 gene

ANGLANI, FRANCA;MURGIA, ALESSANDRA;BEDIN, SILVIA;BERNARDI, FABIOLA;CLEMENTI, MAURIZIO;
1993

Abstract

Neurofibromatosis type 1 (NF 1 ) is one of dm most common autosomal dominant conditions in humans ( 1 in 3000) ( 1 ) and one of the most important inheritable disorders of the nervous system in children. It is characterized by several developmental abnormalities involving tissues of neural crest origin, including an increased incidence of benign and malignant tumors (2) . The NF 1 gene has been ísolated (3 , 4, 5) and has been found to encode an ubiquitous protein, known as neurofibromin (6) . This protein displays a region of homology to human p l20gap , the p2 1 ras GTPase activatíng protein (GAP) (7) . When expressed in non mammalian systems , the GAP-related domain (NF 1 GRD) of the NF 1 gene produces a protein with GAP-like activity which stimulates the intrinsic GTPase actîvity of normal p2 l ras (8) and complements the loss of IRA 1 and IRA2 function in yeast (9) . It has been reeenfly demonstrated that in Schwann eells , neurofibmmín acts as an upstream negative regulator of the proto oncogene ras21 product, strongly supporting the hypothesis that the NF 1 gene is a tumor-suppressor gene ( 10 , 1 1 ) . The characterization of mutauons in the NF 1 gene s]hould also provide clues for the understanding of the molecular basis of the disease and the function of neurofibromin . To date only a few mutatìons of the NE I gene have been described (3 - 5 , 12 - 20). Despíte the large s e of the gene , 1 3 to 1 5 Kb cDNA (2 1 ) , and the high frequency of spontaneous mutations ( 1 × 10 -4/gamete/ generation) ( 1 ) , large and medium size rearrangements are infrequent . This leads to the necessity to screen all the coding sequence , analyzing every single exon of the gene and the intron -exon boundaries , looking for subtle rearrangements and trying to detect regions that might be higly susceptible to mutations. We describe here the molecular study of the NF 1 gene that has been conducted on a sample of 54 NF 1 affected individuals and the identification of a frameshift mutation that has occured in the FLR exon, one of the most conserved parts of the .-NF 1 catalytic domain (NF 1 GRD) ( 1 7).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/2457558
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