International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Hough T
1) MRC Harwell Mammalian Genetics Unit and UK Mouse Genome Centre, 2) Imperial College London

Co-Authors: 3) Fisher E M C, 1) Cheeseman M, 4) Hunter AJ, 1) Brown SDM
Institutions: 1) MRC Harwell Mammalian Genetics Unit and UK Mouse Genome Centre, 3) National Hospital of Neurology and Neurosurgery, London, 4) GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, UK

The study involves characterisation of a mutant mouse line first identified in the biochemical screen of the Harwell ENU Mutagenesis Programme. GENA line 328 mutants display significantly lowered levels of plasma alkaline phosphatase (ALP). Genotyping revealed linkage to Mmu 4. A splice site mutation in the candidate gene (Akp2) was subsequently identified. The mutation causes exon skipping. GENA 328 is of particular interest for the study of the human condition hypophosphatasia - a disorder characterised by skeletal defects resulting from a deficiency of tissue non-specific ALP. Clinical presentation is highly varied and correlation of genotype and phenotype is not clearly understood. GENA 328 homozygous mutants have no visible external phenotype and are alive >12 months after birth. Aged mice develop restricted movement of the large joints in the legs, indicating a late onset skeletal abnormality. X-rays show that by 12 months of age all homozygous mutants develop cartilage hyperplasia of the proximal humerus and the neck of the scapula which forms the shoulder joint. It is possible that these changes result due to weaker (under mineralised) bones that put more strain on these weight-bearing joints in the homozygous mutants. This hypothesis is being investigated using bone densitometry tests. GENA 328 contributes to the mouse phenome database and may further our understanding of hypophosphatasia in humans.

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