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Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects.
Hum Mutat. 1999; 13(3):175-85.HM

Abstract

Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome characterized by parathyroid hyperplasia, pituitary adenomas, and neuroendocrine tumors of the pancreas and duodenum. In 1997, the MEN1 tumor suppressor gene was identified, and numerous germline mutations have been reported to be distributed throughout the gene. We used single strand conformational variant (SSCV) analysis to search for germline mutations in the members of 33 kindreds with a confirmed diagnosis of MEN 1. SSCV analysis revealed 25 conformational variants representing germline mutations that are predicted to result in loss of normal menin function. Twenty different disease-associated mutations were identified: five resulting in potential abnormal RNA splicing, two missense mutations, seven nonsense mutations, and six frameshift mutations. The aberrant splice products were identified and confirmed by RT-PCR and direct sequence analysis for two of the five splice mutations. Sixteen of the 20 (80%) mutations identified have not been previously reported. Mutations were not identified in eight kindreds with signs and symptoms consistent with MEN 1. The SSCV analysis revealed mutations in 76% (25 of 33) of the kindreds investigated, thus showing SSCV analysis to be a reliable mutation detection strategy. One-fifth of the mutations identified in this study involve intron sequences, therefore, highlighting the importance of including intron sequences in the search for germline mutations in the MEN1 gene. The need to investigate the entire gene when characterizing new MEN 1 families presents challenges in the translation of genetic studies to efficient clinical diagnostic tests.

Authors+Show Affiliations

Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10090472

Citation

Mutch, M G., et al. "Germline Mutations in the Multiple Endocrine Neoplasia Type 1 Gene: Evidence for Frequent Splicing Defects." Human Mutation, vol. 13, no. 3, 1999, pp. 175-85.
Mutch MG, Dilley WG, Sanjurjo F, et al. Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. Hum Mutat. 1999;13(3):175-85.
Mutch, M. G., Dilley, W. G., Sanjurjo, F., DeBenedetti, M. K., Doherty, G. M., Wells, S. A., Goodfellow, P. J., & Lairmore, T. C. (1999). Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. Human Mutation, 13(3), 175-85.
Mutch MG, et al. Germline Mutations in the Multiple Endocrine Neoplasia Type 1 Gene: Evidence for Frequent Splicing Defects. Hum Mutat. 1999;13(3):175-85. PubMed PMID: 10090472.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. AU - Mutch,M G, AU - Dilley,W G, AU - Sanjurjo,F, AU - DeBenedetti,M K, AU - Doherty,G M, AU - Wells,S A,Jr AU - Goodfellow,P J, AU - Lairmore,T C, PY - 1999/3/25/pubmed PY - 2000/6/22/medline PY - 1999/3/25/entrez SP - 175 EP - 85 JF - Human mutation JO - Hum Mutat VL - 13 IS - 3 N2 - Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome characterized by parathyroid hyperplasia, pituitary adenomas, and neuroendocrine tumors of the pancreas and duodenum. In 1997, the MEN1 tumor suppressor gene was identified, and numerous germline mutations have been reported to be distributed throughout the gene. We used single strand conformational variant (SSCV) analysis to search for germline mutations in the members of 33 kindreds with a confirmed diagnosis of MEN 1. SSCV analysis revealed 25 conformational variants representing germline mutations that are predicted to result in loss of normal menin function. Twenty different disease-associated mutations were identified: five resulting in potential abnormal RNA splicing, two missense mutations, seven nonsense mutations, and six frameshift mutations. The aberrant splice products were identified and confirmed by RT-PCR and direct sequence analysis for two of the five splice mutations. Sixteen of the 20 (80%) mutations identified have not been previously reported. Mutations were not identified in eight kindreds with signs and symptoms consistent with MEN 1. The SSCV analysis revealed mutations in 76% (25 of 33) of the kindreds investigated, thus showing SSCV analysis to be a reliable mutation detection strategy. One-fifth of the mutations identified in this study involve intron sequences, therefore, highlighting the importance of including intron sequences in the search for germline mutations in the MEN1 gene. The need to investigate the entire gene when characterizing new MEN 1 families presents challenges in the translation of genetic studies to efficient clinical diagnostic tests. SN - 1059-7794 UR - https://www.unboundmedicine.com/medline/citation/10090472/Germline_mutations_in_the_multiple_endocrine_neoplasia_type_1_gene:_evidence_for_frequent_splicing_defects_ L2 - https://doi.org/10.1002/(SICI)1098-1004(1999)13:3<175::AID-HUMU1>3.0.CO;2-R DB - PRIME DP - Unbound Medicine ER -