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Familial polyposiscoli inducing mutatios in APC gene in Poland

100%

Pawlak A. L., Plawski A., Smoczkiewicz P., Kwiatkowska J., Meissner W., Krokiewicz P., West S. P.

vol. 38

issue 1

77-85

Screening for molecular changes within the adenomatous polyposis coli (APC) gene, exons 11 14 and the 5' half of exon 15, encompassing the mutation cluster region within exon 15, was performed in 30 patients with Familial Polyposis Coli (FAP). All patients were studied by heteroduplex analysis (HA) and single strand conformation polymorphism (SSCP) and molecular changes were found in 7 cases. Protein truncation test (PTT) has been performed in 17 cases in which mutations have not been found earlier, and shortening of protein product was noted in 2 cases. In three cases common deletion of 5 bp at codon 1309 and in one 5 bp deletion at codon 1061 were found. In other cases the molecular changes were demonstrated as heteroduplexes in exon 14 (1 patient), in segments E and F (one patient each) of exon 15, and in two cases the heteroduplexes were within the overlapping sequences of segments E/F and F/G of exon 15, respectively. In families where the molecular changes were found by HA, 7 persons at high risk for FAP were found and advised to undergo regular endoscopic examinations. In three persons at risk the transfer of mutation was excluded.

Two novel COL1A1 mutations in patients with osteogenesis imperfecta (OI) affect the stability of the collagen type I triple-helix

88%

Witecka J., Augusciak-Duma A. M., Kruczek A., Szydlo A., Lesiak M., Krzak M., Pietrzyk J. J., Mannikko M., Sieron A. L.

Journal of Applied Genetics

2008

vol. 49

issue 3

283-295

Osteogenesis imperfecta (OI) is a bone dysplasia caused by mutations in the COL1A1 and COL1A2 genes. Although the condition has been intensely studied for over 25 years and recently over 800 novel mutations have been published, the relation between the location of mutations and clinical manifestation is poorly understood. Here we report missense mutations in COL1A1 of several OI patients. Two novel mutations were found in the D1 period. One caused a substitution of glycine 200 by valine at the N-terminus of D1 in OI type I/IV, lowering collagen stability by 50% at 34?C. The other one was a substitution of valine 349 by phenylalanine at the C-terminus of D1 in OI type I, lowering collagen stability at 37.5?C. Two other mutations, reported before, changed amino residues in D4. One was a lethal substitution changing glycine 866 to serine in genetically identical twins with OI type II. That mutated amino acid was near the border of D3 and D4. The second mutation changed glycine 1040 to serine located at the border of D4 and D0.4, in a proband manifesting OI type III, and lowered collagen stability at 39?C (2?C lower than normal). Our results confirm the hypothesis on a critical role of the D1 and D4 regions in stabilization of the collagen triple-helix. The defect in D1 seemed to produce a milder clinical type of OI, whereas the defect in the C-terminal end of collagen type caused the more severe or lethal types of OI.

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2 Journal of Applied Genetics

1 2008

1 1997

1 Augusciak-Duma A. M.

1 Krokiewicz P.

1 Kruczek A.

1 Krzak M.

1 Kwiatkowska J.

1 Lesiak M.

1 Mannikko M.

1 Meissner W.

1 Pawlak A. L.

1 Pietrzyk J. J.

1 Plawski A.

1 Sieron A. L.

1 Smoczkiewicz P.

1 Szydlo A.

1 West S. P.

1 Witecka J.

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Familial polyposiscoli inducing mutatios in APC gene in Poland

Two novel COL1A1 mutations in patients with osteogenesis imperfecta (OI) affect the stability of the collagen type I triple-helix