Keratin 8 mutations in patients with cryptogenic liver disease.

被引:138
作者
Ku, NO
Gish, R
Wright, TL
Omary, MB
机构
[1] Vet Affairs Med Ctr, Gastroenterol Sect, Palo Alto, CA 94304 USA
[2] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA
[3] Calif Pacific Med Ctr, Dept Transplantat, San Francisco, CA USA
[4] Vet Affairs Med Ctr, Gastroenterol Sect, San Francisco, CA 94121 USA
关键词
D O I
10.1056/NEJM200105243442103
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: About 10 percent of patients who undergo liver transplantation have cryptogenic liver disease. In animal models, the absence of heteropolymeric keratins 8 and 18 or the presence of mutant keratins in hepatocytes causes or promotes liver disease. We have previously described a mutation in the keratin 18 gene in a patient with cryptogenic cirrhosis, but the importance of mutations in the keratin 8 and keratin 18 genes in such patients is unclear. Methods: We tested for mutations in the keratin 8 and keratin 18 genes in purified genomic DNA isolated from 150 explanted livers and 89 peripheral-blood specimens from three groups of patients: 55 patients with cryptogenic liver disease; 98 patients with noncryptogenic liver disease, with causes that included alcohol use, autoimmunity, drug use, and viral infections; and 86 randomly selected inpatients and outpatients who provided blood to the hematology laboratory. Results: Of the 55 patients with cryptogenic liver disease, 3 had glycine-to-cysteine mutations at position 61 (a highly conserved glycine) of keratin 8, and 2 had tyrosine-to-histidine mutations at position 53 of keratin 8. These mutations were not detected in the patients with other liver diseases or in the randomly selected patients. In transfected cells, the glycine-to-cysteine mutation limited keratin-filament reorganization when the cells were exposed to oxidative stress. In contrast, the tyrosine-to-histidine mutation destabilized keratin filaments when transfected cells were exposed to heat or okadaic acid stress. Conclusions: Mutations in the keratin 8 gene may predispose people to liver disease and may account for cryptogenic liver disease in some patients. (N Engl J Med 2001;344:1580-7.) Copyright (C) 2001 Massachusetts Medical Society.
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页码:1580 / 1587
页数:8
相关论文
共 53 条
[1]   COLORECTAL HYPERPLASIA AND INFLAMMATION IN KERATIN 8-DEFICIENT EVB/N MICE [J].
BARIBAULT, H ;
PENNER, J ;
IOZZO, RV ;
WILSONHEINER, M .
GENES & DEVELOPMENT, 1994, 8 (24) :2964-2973
[2]   MIDGESTATIONAL LETHALITY IN MICE LACKING KERATIN-8 [J].
BARIBAULT, H ;
PRICE, J ;
MIYAI, K ;
OSHIMA, RG .
GENES & DEVELOPMENT, 1993, 7 (7A) :1191-1202
[3]   Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy [J].
Bonne, G ;
Di Barletta, MR ;
Varnous, S ;
Bécane, HM ;
Hammouda, EH ;
Merlini, L ;
Muntoni, F ;
Greenberg, CR ;
Gary, F ;
Urtizberea, JA ;
Duboc, D ;
Fardeau, M ;
Toniolo, D ;
Schwartz, K .
NATURE GENETICS, 1999, 21 (03) :285-288
[4]   Cryptogenic cirrhosis: Clinical characterization and risk factors for underlying disease [J].
Caldwell, SH ;
Oelsner, DH ;
Iezzoni, JC ;
Hespenheide, EE ;
Battle, EH ;
Driscoll, CJ .
HEPATOLOGY, 1999, 29 (03) :664-669
[5]   Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy [J].
Cao, H ;
Hegele, RA .
HUMAN MOLECULAR GENETICS, 2000, 9 (01) :109-112
[6]   THE GENETIC-BASIS OF WEBER-COCKAYNE EPIDERMOLYSIS-BULLOSA SIMPLEX [J].
CHAN, YM ;
YU, QC ;
FINE, JD ;
FUCHS, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (15) :7414-7418
[7]  
Charlton M R, 1997, Liver Transpl Surg, V3, P359, DOI 10.1053/jlts.1997.v3.pm0009346764
[8]   A LEUCINE-]PROLINE MUTATION IN THE H1 SUBDOMAIN OF KERATIN-1 CAUSES EPIDERMOLYTIC HYPERKERATOSIS [J].
CHIPEV, CC ;
KORGE, BP ;
MARKOVA, N ;
BALE, SJ ;
DIGIOVANNA, JJ ;
COMPTON, JG ;
STEINERT, PM .
CELL, 1992, 70 (05) :821-828
[9]  
Covello SP, 1998, BRIT J DERMATOL, V139, P475
[10]   Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. [J].
Dalakas, MC ;
Park, KY ;
Semino-Mora, C ;
Lee, HS ;
Sivakumar, K ;
Goldfarb, LG .
NEW ENGLAND JOURNAL OF MEDICINE, 2000, 342 (11) :770-780