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Mutations in the COL1A1 and COL1A2 genes associated with osteogenesis imperfecta (OI) types I or III

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Augusciak-Duma A., Witecka J., Sieron A., Janeczko M., Pietrzyk J., Ochman K., Galicka A., Borszewska-Kornacka M., Pilch J., Jakubowska-Pietkiewicz E.

Acta Biochimica Polonica

2018

vol. 65

issue 1

79-86

Although over 85% of osteogenesis imperfecta (OI) cases are associated with mutations in the procollagen type I genes (COL1A1 or COL1A2), no hot spots for the mutations were associated with particular clinical phenotypes. Eight patients that were studied here, diagnosed with OI by clinical standards, are from the Polish population with no ethnic background indicated. Previously unpublished mutations were found in six out of those eight patients. Genotypes for polymorphisms (Sp1 - rs1800012 and PvuII - rs412777), linked to bone formation and metabolism were determined. Mutations were found in exons 2, 22, 50 and in introns 13 and 51 of the COL1A1 gene. In COL1A2, one mutation was identified in exon 22. Deletion type mutations in COL1A1 that resulted in OI type I had no effect on collagen type I secretion, nor on its intracellular accumulation. Also, a single base substitution in I13 (c.904-9 G>T) was associated with the OI type I. The OI type III was associated with a single base change in I51 of COL1A1, possibly causing an exon skipping. Also, a missense mutation in COL1A2 changing Gly→Cys in the central part of the triple helical domain of the collagen type I molecule caused OI type III. It affected secretion of the heterotrimeric form of procollagen type I. However, no intracellular accumulation of procollagen chains could be detected. Mutation in COL1A2 affected its incorporation into procollagen type I. The results obtained shall help in genetic counseling of OI patients and provide a rational support for making informed, life important decisions by them and their families.

Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness

81%

Bik-Multanowski M., Kaluzny L., Mozrzymas R., Oltarzewski M., Starostecka E., Lange A., Didycz B., Gizewska M., Ulewicz-Filipowicz J., Chrobot A., Mikoluc B., Szymczakiewicz-Multanowska A., Cichy W., Pietrzyk J.

Acta Biochimica Polonica

2013

vol. 60

issue 4

613-616

Tetrahydrobiopterin (BH4) has been recently approved as a treatment of patients with phenylketonuria. However, as a confirmation of BH4-responsiveness, it might require a very expensive trial treatment with BH4 or prolonged BH4-loading procedures. The selection of patients eligible for BH4-therapy by means of genotyping of the PAH gene mutations may be recommended as a complementary approach. A population-wide genotyping study was carried out in 1286 Polish phenyloketonuria-patients. The aim was to estimate the BH4 demand and to cover prospectively the treatment by a National Health Fund. A total of 95 types of mutations were identified. Genetic variants corresponding with probable BH4-responsiveness were found in 28.2% of cases. However, patients with mild or classical phenylketonuria who require continuous treatment accounted for 11.4% of the studied population only. Analysis of the published data shows similar percentage of the "BH4-responsive" variants of a PAH gene in patients from other countries of Eastern Europe. Therefore, it can be concluded, that the proportion of phenylketonuria-patients who could benefit from the use of BH4 reaches approximately 10% in the entire region.

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2 Acta Biochimica Polonica

1 2018

1 2013

2 Pietrzyk J.

1 Augusciak-Duma A.

1 Bik-Multanowski M.

1 Borszewska-Kornacka M.

1 Chrobot A.

1 Cichy W.

1 Didycz B.

1 Galicka A.

1 Gizewska M.

1 Jakubowska-Pietkiewicz E.

1 Janeczko M.

1 Kaluzny L.

1 Lange A.

1 Mikoluc B.

1 Mozrzymas R.

1 Ochman K.

1 Oltarzewski M.

1 Pilch J.

1 Sieron A.

1 Starostecka E.

1 Szymczakiewicz-Multanowska A.

1 Ulewicz-Filipowicz J.

1 Witecka J.

Search results

Mutations in the COL1A1 and COL1A2 genes associated with osteogenesis imperfecta (OI) types I or III

Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness