Witecka Joanna, Auguściak-Duma Aleksandra M, Kruczek Anna, Szydło Anna, Lesiak Marta, Krzak Maria, Pietrzyk Jacek J, Männikkö Minna, Sieroń Aleksander L
Department of General and Molecular Biology and Genetics, Medical University of Silesia, Katowice, Poland.
J Appl Genet. 2008;49(3):283-95. doi: 10.1007/BF03195625.
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 degrees 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 degrees 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 degrees C (2 degrees 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.
成骨不全症（OI）是一种由COL1A1和COL1A2基因突变引起的骨发育异常疾病。尽管对该疾病进行了25年多的深入研究，最近也发表了800多个新突变，但突变位置与临床表现之间的关系仍知之甚少。在此，我们报告了几例OI患者COL1A1基因中的错义突变。在D1期发现了两个新突变。一个突变导致I/IV型OI中D1的N端甘氨酸200被缬氨酸取代，在34℃时胶原稳定性降低50%。另一个突变是I型OI中D1的C端缬氨酸349被苯丙氨酸取代，在37.5℃时降低了胶原稳定性。另外两个之前报道的突变改变了D4中的氨基酸残基。一个是致死性取代，在患有II型OI的同卵双胞胎中将甘氨酸866变为丝氨酸。该突变氨基酸靠近D3和D4的边界。第二个突变将甘氨酸1040变为丝氨酸，位于D4和D0.4的边界，在一名表现为III型OI的先证者中，在39℃时降低了胶原稳定性（比正常低2℃）。我们的结果证实了关于D1和D4区域在胶原三螺旋稳定中起关键作用的假设。D1中的缺陷似乎导致OI的临床类型较轻，而I型胶原C端的缺陷则导致更严重或致死性的OI类型。
