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A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis.

ABSTRACT: North American Indian childhood cirrhosis (CIRH1A, or NAIC), a severe autosomal recessive intrahepatic cholestasis described in Ojibway-Cree children from northwestern Quebec, is one of several familial cholestases with unknown molecular etiology. It typically presents with transient neonatal jaundice, in a child who is otherwise healthy, and progresses to biliary cirrhosis and portal hypertension. Clinical and physiological investigations have not revealed the underlying cause of the disease. Currently, liver transplantation is the only effective therapy for patients with advanced disease. We previously identified the NAIC locus by homozygosity mapping to chromosome 16q22. Here we report that an exon 15 mutation in gene FLJ14728 (alias Cirhin) causes NAIC: c.1741C-->T in GenBank cDNA sequence NM_032830, found in all NAIC chromosomes, changes the conserved arginine 565 codon to a tryptophan, altering the predicted secondary structure of the protein. Cirhin is preferentially expressed in embryonic liver, is predicted to localize to mitochondria, and contains WD repeats, which are structural motifs frequently associated with molecular scaffolds.

SUBMITTER: Chagnon P

PROVIDER: S-EPMC378590 | biostudies-literature | 2002 Dec

REPOSITORIES: biostudies-literature

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A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis.

Chagnon Pierre P Michaud Jacques J Mitchell Grant G Mercier Jocelyne J Marion Jean-François JF Drouin Eric E Rasquin-Weber Andrée A Hudson Thomas J TJ Richter Andrea A

American journal of human genetics 20021104 6

North American Indian childhood cirrhosis (CIRH1A, or NAIC), a severe autosomal recessive intrahepatic cholestasis described in Ojibway-Cree children from northwestern Quebec, is one of several familial cholestases with unknown molecular etiology. It typically presents with transient neonatal jaundice, in a child who is otherwise healthy, and progresses to biliary cirrhosis and portal hypertension. Clinical and physiological investigations have not revealed the underlying cause of the disease. C ...[more]

PMID: 12417987

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Project description:North American Indian Childhood Cirrhosis (NAIC) is a rare, autosomal recessive, progressive cholestatic disease of infancy affecting the Cree-Ojibway first Nations of Quebec. All NAIC patients are homozygous for a missense mutation (R565W) in CIRH1A, the human homolog of the yeast nucleolar protein Utp4. Utp4 is part of the t-Utp subcomplex of the small subunit (SSU) processome, a ribonucleoprotein complex required for ribosomal RNA processing and small subunit assembly. NAIC has thus been proposed to be a primary ribosomal disorder (ribosomopathy); however, investigation of the pathophysiologic mechanism of this disease has been hindered by lack of an animal model. Here, using a morpholino oligonucleotide (MO)-based loss-of-function strategy, we have generated a model of NAIC in the zebrafish, Danio rerio. Zebrafish Cirhin shows substantial homology to the human homolog, and cirh1a mRNA is expressed in developing hepatocytes and biliary epithelial cells. Injection of two independent MOs directed against cirh1a at the one-cell stage causes defects in canalicular and biliary morphology in 5 dpf larvae. In addition, 5 dpf Cirhin-deficient larvae have dose-dependent defects in hepatobiliary function, as assayed by the metabolism of an ingested fluorescent lipid reporter. Previous yeast and in vitro studies have shown that defects in ribosome biogenesis cause stabilization and nuclear accumulation of p53, which in turn causes p53-mediated cell cycle arrest and/or apoptosis. Thus, the nucleolus appears to function as a cellular stress sensor in some cell types. In accordance with this hypothesis, transcriptional targets of p53 are upregulated in Cirhin-deficient zebrafish embryos, and defects in biliary function seen in Cirhin-deficient larvae are completely abrogated by mutation of tp53. Our data provide the first in vivo evidence of a role for Cirhin in biliary development, and support the hypothesis that congenital defects affecting ribosome biogenesis can activate a cellular stress response mediated by p53.

Project description:OBJECTIVES:The objective of this study was to examine the association among psychological and social variables reported by American Indian parents/caregivers of preschool children and changes in their Oral Health Knowledge and Behaviors related to care of their children's teeth. We also investigated the relationship of these factors with progression of caries, as reflected by changes in their children's dmfs. METHODS:The data used for this study were collected at baseline in a clinical trial of an oral health promotion intervention comprising behavioural and clinical interventions for caries prevention delivered by tribal members on a large Southwestern American Indian reservation. Linear regression analyses were performed for changes (baseline to Year 1) in dmfs, Oral Health Knowledge and Oral Health Behavior scores, with baseline psychosocial measures, taken individually, as the independent variables. RESULTS:Parents' attitudes and beliefs were associated with increases in their Oral Health Knowledge and Behavior and also with the progression of caries for their children. When all participants were considered together, increases in children's dmfs were smaller when the caregiver had higher Internal Oral Health Locus of Control (e = -1.33, P = .004), higher Health Literacy (e = -1.55, P < .01), and higher Financial Stability (e = -4.46, P = .03), and lower scores for the Barriers subscale (e = 1.57, P < .01) of the Health Belief Model. For parents in the Intervention group, higher scores on Locus of Control, reflecting beliefs that chance, or other people determine their children's oral health, were associated with larger increases in Oral Health Knowledge (e = 1.73, P = .04) and Behaviors (e = 4.00, P = .005). CONCLUSIONS:Prevention of early childhood caries in American Indian children has proved to be especially challenging. Some of the measures identified in this report may suggest promising directions to prevention through approaches that build on competencies and skills to be learned and used within a context more broadly focused on parenting and management of health and family challenges.

Dataset Information

A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis.

Publications

A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis.

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