Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia

被引：42

作者：

Nürnberg P. ^{[1
,2
]}

Thiele H. ^{[1
,2
]}

Chandler D. ^{[3
]}

Höhne W. ^{[4
]}

Cunningham M.L. ^{[5
]}

Ritter H. ^{[1
]}

Leschik G. ^{[1
]}

Uhlmann K. ^{[1
]}

Mischung C. ^{[1
]}

Harrop K. ^{[6
]}

Goldblatt J. ^{[6
]}

Borochowitz Z.U. ^{[7
]}

Kotzot D. ^{[8
]}

Westermann F. ^{[9
]}

Mundlos S. ^{[1
]}

Braun H.-S.

Laing N. ^{[3
]}

Tinschert S. ^{[1
]}

机构：

[1] Institut für Medizinische Genetik, Universitätsklinikum Charité, Humboldt-Universität, Berlin

[2] Gene Mapping Center, Max-Delbrück Center for Molecular Medicine, Berlin-Buch

[3] Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, Nedlands, WA

[4] Institut für Biochemie, Universitätsklinikum Charité, Humboldt-Universität, Berlin

[5] Children's Craniofacial Center, Department of Pediatrics, University of Washington, Seattle, WA

[6] Genetic Services, Health Department of Western Australia, King Edward Memorial Hospital, Subiaco, WA

[7] Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, Technion-Faculty of Medicine

[8] Institut für Medizinische Genetik, Universität Zürich, Zürich

[9] Endokrinologische Ambulanz, Universitätskinderklinik Köln, Cologne

来源：

Nature Genetics | 2001年 / 28卷 / 1期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1038/ng0501-37

中图分类号：

学科分类号：

摘要：

Craniometaphyseal dysplasia (CMD) is a bone dysplasia characterized by overgrowth and sclerosis of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones. Hyperostosis and sclerosis of the skull may lead to cranial nerve compressions resulting in hearing loss and facial palsy1,2. An autosomal dominant form of the disorder (MIM 123000) was linked to chromosome 5p5.2-p14.1 (ref. 3) within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene4. The ANK protein spans the outer cell membrane and shuttles inorganic pyrophosphate4 (PPi), a major inhibitor of physiologic and pathologic calcification, bone mineralization and bone resorption5. Here we carry out mutation analysis of ANKH, revealing six different mutations in eight of nine families. The mutations predict single amino acid substitutions, deletions or insertions. Using a helix prediction program, we propose for the ANK molecule 12 membrane-spanning helices with an alternate inside/out orientation and a central channel permitting the passage of PPi. The mutations occur at highly conserved amino acid residues presumed to be located in the cytosolic portion of the protein. Our results link the PPi channel ANK with bone formation and remodeling.

引用

页码：37 / 41

页数：4

共 18 条

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