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PMID:9916809

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Citation

Munroe, PB, Olgunturk, RO, Fryns, JP, Van Maldergem, L, Ziereisen, F, Yuksel, B, Gardiner, RM and Chung, E (1999) Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat. Genet. 21:142-4

Abstract

Keutel syndrome (KS, MIM 245150) is an autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and midfacial hypoplasia. A genome search using homozygosity mapping provided evidence of linkage to chromosome 12p12.3-13.1 (maximum multipoint lod score, 4.06). MGP was a candidate on the basis of its localization to this chromosomal region and the known function of its protein. MGP maps to chromosome 12p near D12S363. Human MGP is a 10-kD skeletal extracellular matrix (ECM) protein that consists of an 84-aa mature protein and a 19-aa transmembrane signal peptide. It is a member of the Gla protein family, which includes osteocalcin, another skeletal ECM protein, and a number of coagulation factors (factors II, VII, IX, X and proteins S and C). All members of this family have glutamic acid residues modified to gamma-carboxyglutamic acids (Gla) by a specific gamma-carboxylase using vitamin K as a cofactor. The modified glutamic acid residues of Gla proteins confer a high affinity for mineral ions such as calcium, phosphate and hydroxyapatite crystals, the mineral components of the skeletal ECM. The pattern and tissue distribution of Mgp expression in mice suggest a role for Mgp in regulating ECM calcification. Mglap-deficient mice (Mglap-/-) have been reported to have inappropriate calcification of cartilage. Mutational analysis of MGP in three unrelated probands identified three different mutations: c.69delG, IVS1-2A-->G and c.113T-->A. All three mutations predict a non-functional MGP. Our data indicate that mutations in MGP are responsible for KS and confirm its role in the regulation of extracellular matrix calcification.

Links

PubMed Online version:10.1038/5102

Keywords

Abnormalities, Multiple/genetics; Abnormalities, Multiple/physiopathology; Calcium-Binding Proteins/genetics; Chromosome Deletion; Chromosomes, Human, Pair 12; Extracellular Matrix Proteins; Female; Humans; Male; Mutation; Pedigree; Syndrome

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MGP

located_in

GO:0031012: extracellular matrix

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MGP

involved_in

GO:0001502: cartilage condensation

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MGP

involved_in

GO:0001503: ossification

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MGP

enables

GO:0005201: extracellular matrix structural constituent

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MGP

part_of

GO:0031012: extracellular matrix

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MGP

enables

GO:0008147: structural constituent of bone

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete


See also

References

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