Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency.: Value of the OTC structure in predicting a mutation pathogenic potential
Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency.: Value of the OTC structure in predicting a mutation pathogenic potential
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DOI：
10.1007/s10545-007-0429-x
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发表时间：
2007-04-01
影响因子：
4.2
通讯作者：
Rubio, V.
中科院分区：
文献类型：
--
作者：
Arranz, J. A.;Riudor, E.;Rubio, V.
鸟氨酸转氨甲酰酶缺乏症（OTCD）是一种X连锁的最常见的尿素循环错误，由编码354个残基多肽的OTC基因突变引起。迄今为止，已经汇编了341个OTCD临床突变，包括222个错义单核苷酸变化（mSNC）（MITUATMutat 2006;27：626）。如果已知引起OTCD的突变的全部谱，则OTCD突变检测可能被简化。我们从23名表现出22种不同突变的新OTCD患者中估计了该库的大小，其中9种，包括4种mSNCs，是新的。导致OTCD的突变的完整库估计为560个突变（95%置信区间，422-833个突变），包括290个mSNC（95%置信区间，230394个mSNC）。因此，基于已知突变筛查的OTCD诊断可能在< 5年内达到类似于90%的灵敏度。由于致病mSNCs占2064种可能的OTC mSNCs的< 20%，因此简单的方法对于区分致病mSNCs和普通mSNCs至关重要。OTC结构的观察似乎是一种简单的鉴别方法，在我们的样品中与三种正式的基于结构和/或基于序列的计算机模拟评估方法进行了有利的比较，并支持突变p.Pro305Arg和p.Ser96Phe导致完全缺陷，以及p.Asp41Gly、p.Glu122Gly、p.Leu179Phe、p.Pro220Thr和p.Glu273del导致部分缺陷的原因。5个非mSNC新突变（p.Gly71X，外显子5的7个核苷酸和10个核苷酸的重复和缺失，内含子4和9的碱基+1和+5的G > A转运离子）是明显致病的。本文还讨论了本研究中发现的p.Arg26Gln、p.Arg40His、p.Glu52Lys、p.Lys88Asn、p.Arg129His、P-Asn 161 Ser、p.Thr178Met、p.His202Tyr、p.Ala208Thr和p.His302Arg等mSNCs。
Ornithine transcarbamylase deficiency (OTCD), the X-linked, most frequent urea cycle error, results from mutations in the OTC gene, encoding a 354-residue polypeptide. To date 341 OTCD clinical mutations, including 222 missense single nucleotide changes (mSNCs), have been compiled (Hum Mutat 2006;27:626). OTCD mutation detection might be simplified if the entire repertoire of OTCD-causing mutations were known. We estimate the size of this repertoire from 23 new OTCD patients exhibiting 22 different mutations, of which 9, including 4 mSNCs, are novel. The complete repertoire of OTCD-causing mutations is estimated as 560 mutations (95% confidence interval, 422-833 mutations), including 290 mSNCs (95% confidence interval, 230394 mSNCs). Thus, OTCD diagnosis based on the screening for known mutations might attain similar to 90% sensitivity in < 5 years. Since disease-causing mSNCs represent < 20% of the 2064 possible OTC mSNCs, simple approaches are essential for discrimination between causative and trivial mSNCs. Observation of the OTC structure appears a simple approach for such discrimination, comparing favourably in our sample with three formalized structure-based and/or sequence-based in silico,assessment methods, and supporting the causation of complete deficiency by the mutations p.Pro305Arg and p.Ser96Phe, and of partial deficiency by p.Asp41Gly, p.Glu122Gly, p.Leu179Phe, p.Pro220Thr and p.Glu273del. Five non-mSNC novel mutations (p.Gly71X, a 7-nucleotide and a 10-nucleotide duplication and deletion in exon 5, G > A transit ions at bases +1 and +5 of introns 4 and 9, respectively) are obviously pathogenic. The previously reported mSNCs p.Arg26Gln, p.Arg40His, p.Glu52Lys, pLys88Asn, p.Arg129His, P-Asn161Ser, p.Thr178Met, p.His202Tyr, p.Ala208Thr and p.His302Arg, found in our cohort, are also discussed.