Genetic mapping studies of 40 loci and 23 cosmids in chromosome 11p13-11q13, and exclusion of Ì-calpain as the multiple endocrine neoplasia type 1 gene

Abstract

Forty loci (16 polymorphic and 24 non-polymorphic) together with 23 cosmids isolated from a chromosome 11-specific library were used to construct a detailed genetic map of 11p13-11q13. The map was constructed by using a panel of 13 somatic cell hybrids that sub-divided this region into 19 intervals, a meiotic mapping panel of 33 multiple endocrine neoplasia type 1 (MEN1) families (134 affected and 269 unaffected members) and a mitotic mapping panel that was used to identify loss of heterozygosity in 38 MEN1-associated tumours. The results defined the most likely order of the 16 loci as being: 11pter-D11S871-(D11S288, D11S149)-11cen-CNTF-PGA-ROM1-D11S480-PYGM- SEA-D11S913-D11S970-D11S97- D11S146-INT2-D11S971-D11S533-11qter. The meiotic mapping studies indicated that the most likely location of the MEN1 gene was in the interval flanked by PYGM and D11S97, and the results of mitotic mapping suggested a possible location of the MEN1 gene telomeric to SEA. Mapping studies of the gene encoding mu-calpain (CAPN1) located CAPN1 to 11q13 and in the vicinity of the MEN1 locus. However, mutational analysis studies did not detect any germ-line CAPN1 DNA sequence abnormalities in 47 unrelated MEN1 patients and the results therefore exclude CAPN1 as the MEN1 gene. The detailed genetic map that has been constructed of the 11p13-11q13 region should facilitate the construction of a physical map and the identification of candidate genes for disease loci mapped to this region.

A Transcript Map for the 2.8-Mb Region Containing the Multiple Endocrine Neoplasia Type 1 Locus

“…Previous reports include only two transcripts, ZFM1 and FAU1 (Kas et al 1993b), in this interval, both of which had been excluded by mutation analysis as candidate genes for MEN1. Another gene, CAPN1 (Pang et al 1996), excluded previously by mutation analysis, also maps to this region. LOH studies in MEN 1 and sporadic tumors with several new markers have subsequently resulted in narrowing the MEN1 locus to a 300-kb PYGM-D11S4936 region , though the distal boundary has to be considered provisional because it was based on LOH in a sporadic gastrinoma.…”

Modulation of the activity of calcium-activated neutral proteases (calpains) in chronic lymphocytic leukemia (B-CLL) cells

“…[9][10][11]17 Increased activity of -calpain that we observe in B-CLL cells may be related to at least some of the mutations found in the genome of these leukemic cells. Genetic disorders associated with B-CLL concern mostly the 11 and 13 chromosomes, whereas the genes for -and m-calpains are located, respectively, in the 11th (11q13) [5][6][7][8]54 and first 55 chromosome. In fact, Brizard et al find in the B-CLL rare translocations and deletions precisely in the 11q13 band of the 11th chromosome containing the calpain gene.…”

Mapping the Gene Causing Hereditary Primary Hyperparathyroidism in a Portuguese Kindred to Chromosome 1q22-q31

“…(7,19,30,31) Fifteen polymorphic microsatellite loci (D1S104, D1S196, D1S212, D1S215, D1S254, D1S222, D1S202, D1S238, D1S428, D1S2877, D1S422, D1S412, D1S306, D1S429, and D1S245) from chromosome 1q, three such loci (D1S228, D1S507, and D1S220) from chromosome 1p, and the polymorphic Rb locus (Rb1.20) from chromosome 13q14 were utilized as reported. (7,19,30,31) The microsatellite polymorphisms obtained from the tumors were compared with those from the leukocytes of the same patient, and a LOH in the tumors was scored only if there was an absence or a marked reduction in the visually assessed intensity of one of the bands. From patient III.14, leukocyte DNA was not available and LOH studies of the tumor DNA were therefore HEREDITARY PRIMARY HYPERPARATHYROIDISM 231 not possible.…”