Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase

被引：116

作者：

Dimmock, D. P. ^{[1
]}

Zhang, Q. ^{[1
]}

Dionisi-Vici, C. ^{[2
]}

Carrozzo, R. ^{[3
]}

Shieh, J. ^{[4
]}

Tang, L. Y. ^{[1
]}

Truong, C. ^{[1
]}

Schmitt, E. ^{[1
]}

Sifry-Platt, M. ^{[5
]}

Lucioli, S. ^{[3
]}

Santorelli, F. M. ^{[3
]}

Ficicioglu, C. H. ^{[6
]}

Rodriguez, M. ^{[7
]}

Wierenga, K. ^{[8
]}

Enns, G. M. ^{[9
]}

Longo, N. ^{[10
]}

Lipson, M. H. ^{[5
]}

Valiance, H. ^{[11
]}

Craigen, W. J. ^{[1
]}

Scaglia, F. ^{[1
]}

Wong, L-J. ^{[1
]}

机构：

[1] Baylor Coll Med, Dept Human Mol Genet, Houston, TX 77030 USA

[2] Childrens Hosp Bambino Gesu, Div Metab, Rome, Italy

[3] Childrens Hosp Bambino Gesu, Mol Med Unit, Rome, Italy

[4] Univ Calif San Francisco, J David Gladstone Inst, San Francisco, CA USA

[5] Kaiser Permanente, Dept Med Genet, Sacramento, CA USA

[6] Childrens Hosp Philadelphia, Metab Sect, Philadelphia, PA USA

[7] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL USA

[8] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn, Ctr Genet Med, Miami, FL USA

[9] Stanford Univ, Sch Med, Div Med Genet, Stanford, CA USA

[10] Univ Utah, Dept Pediat, Div Med Genet, Salt Lake City, UT 84112 USA

[11] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada

来源：

HUMAN MUTATION | 2008年 / 29卷 / 02期

关键词：

hepatoencephalopathy; mtDNA depletion syndrome; mitochondrial cytopathy; neuropathy; viral hepatitis cholestasis; cirrhosis; dGK; DGUOK; acute liver failure;

D O I：

10.1002/humu.9519

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Published mutations in deoxyguanosine kinase (DGUOK) cause mitochondrial DNA depletion and a clinical phenotype that consists of neonatal liver failure, nystagmus and hypotonia. In this series, we have identified 15 different mutations in the DGUOK gene from 9 kindreds. Among them, 12 have not previously been reported. Nonsense, splice site, or frame-shift mutations that produce truncated proteins predominate over missense mutations. All patients who harbor null mutations had early onset liver failure and significant neurological disease. These patients have all died before 2-years of age. Conversely, two patients carrying missense mutations had isolated liver disease and are alive in their 4th year of life without liver transplant. Five subjects were detected by newborn screening, with elevated tyrosine or phenylalanine. Consequently, this disease should be considered if elevated tyrosine is identified by newborn screening. Mitochondrial DNA content was below 10% of controls in liver in all but one case and modestly reduced in blood cells. With this paper a total of 39 different mutations in DGUOK have been identified. The most frequent mutation, c.763_c-766dupGATT, occurs in 8 unrelated kindreds. 70% of mutations occur in only one kindred, suggesting full sequencing of this gene is required for diagnosis. The presentation of one case with apparent viral hepatitis, without neurological disease, suggests that this disease should be considered in patients with infantile liver failure regardless of the presence of neurological features or apparent infectious etiology. (C) 2007 Wiley-Liss, Inc.

引用

页码：330 / 331

页数：2