Germline profile of men 1 gene in nineteen unrelated cases borned in argentina.

PATRICIA FAISNTEIN DAY; TOMÁS FERNANDEZ GIANOTTI; MARÍA LORENA VIALE; ADRIANA DIAZ; DÉBORAH KATZ; ANDREA KOZAK; MARTA BALZARETTI; MARÍA PIA SERRA; ESCOBAR MARÍA EUGENIA; ROMINA P. GRINSPON; OSCAR BRUNO

Gubbio, Italy.

Congreso; 12th International Workshops of multiple endocrine neoplasia.; 2010

Multiple Endocrine Neoplasia type 1 (MEN 1) is an uncommon syndrome characterized by the presence of two or more endocrine tumors typically located in parathyroids, enteropancreas and/or anterior pituitary and has an autosomal dominant pattern of inheritance. MEN1 gene mapped to chromosome 11q13 and more than a thousand mutations have been reported that are located all along the gene. The germinal mutation detection rate is between 24 to 80% probably because of differences in selection of patients. Of the germline mutations found approximately 41% were frameshift deletions or insertions (fs), 23% nonsense mutations (ns), 20% missense mutations (ms), 9% splice site mutations and 6% in-frame deletions or insertions and 1% whole or partial gene deletions.  The aim of our investigation was the genetic study of 36 potential carriers borned in Argentina.   Subjets and Methods: Seventeen classic index patients defined as harboring at least two typical tumors and 2  non-classic index patients defined as having one typical tumor and less than 18 years old. Besides, 17  relatives of 5 patients with germinal mutation were included. Genomic DNA was extracted from peripheral blood leukocytes. Exons 2 to 10 of MEN1 gene were amplified by PCR and sequenced by ddNTP33 or an automated method. DNA was isolated from peripheral blood of 54 argentinian blood donors. Both alelles from exons 3 and 10 were sequenced in order to determine the population frecuence of non pathogenic aminoacids sustitution.   Results: Genetic profile of index cases are shown in the table. We found mutations in 73.6% of index cases and polimorfism (pol) only in 15.7%, no changes in normal sequence was foud in two of them (10.5%). Of the mutations found,  50% were fs, 35.7% were ms and 14.3% were ns.   Conclusions. We found germinal mutations in 73.6 % of classic index patients, in 2/2 non classic index patients and in 47% of  relatives. Interestingl,in our patients, a larger proportion of missense mutations than reported by others, was found.     Index  Case Sex Age (years) Mutation (Ref Seq NM_130799.1) Exon Predicted effect Novel germline mutations 1 F 15 c.249_252delGTCT 2 fs   2 M 30 c.625_628delCAGA 3 fs   3 F 47 c.1127T>C 8 ms,L376P * 4 M 40 c.1060_1063dupTGCC 8 fs * 5 F 42 c.1405G>T 10 ns, E469X * 6 F 42 c.1621G>A 10 pol, A541T   7 F 49 ------- ----- -----   8 M 28 c.1340T>C 9 ms,F447S   9 F 38 c.378delG c.512G>A 2 3 fs pol, R171Q * 10 F 30 c.1664G>T 10 ms,S555I * 11 F 30 c.1254C>T 10 pol , D418D   12 F 30 c.1340T>C 9 ms,F447S   13 F