Mouse Genome Informatics
hm
    Pla2g6tm1Tsu/Pla2g6tm1Tsu
involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• the median lifespan is 90 weeks which is significantly shorter than the 110-115 week median age of littermate controls

reproductive system
• male mice exhibit reduced fertility similar to male Pla2g6tm1Turk homozygotes (J:132853)

growth/size/body
• mice gradually lose weight after 50 weeks of age with significant differences in body weight occurring by 91-100 weeks of age

behavior/neurological
• mice exhibit dragging of hind limbs by 2 years of age
• all 2 year old mice show impaired motor function in a hanging wire test
• impairment in ability to hang from wire is evident at 30 weeks of age and all mice demonstrate very low time scores by 50 weeks of age
• 2 year old mice exhibit abnormal movement of hind-limbs
• when held by the tail, 2 year old mice move their hind-limbs in random directions or stop moving with their feet clasp
• control mice spread hind limbs to maintain balance
• mice exhibit an irregular stride by 2 years of age

nervous system
• mutants exhibit progressive increase in periodic acid-Schiff (PAS)-positive granules, first seen in the proximal axons and perinuclear space of large neurons and later in distal parts of axons
• granules are mitochondria with degenerative inner membranes
• collapse of mitochondria in axons is accompanied by focal disappearance of the cytoskeleton
• at 15 weeks of age, myelin splitting is observed in the sciatic nerve
• at 56 weeks of age, myelin ovoids are observed and large fibers exhibit redundant, split or thin myelin in the sciatic nerve
• insufficient remodeling and degeneration of presynaptic membranes
• degeneration of presynaptic membranes at axon terminals results in appearance of tubulovesicular structures
• the area of myelinated fibers within the sciatic nerve is significantly smaller in 2 year old mice than in age-matched wild-type control mice (J:132853)
• PAS+ granules start to be seen in the large fibers of the sciatic nerve at 15 weeks of age, are increased in number and size at 56 weeks and by 100 weeks, granules are seen in both large and small fibers of the sciatic nerve (J:174587)
• large fibers in the sciatic nerve are decreased in number at 56 weeks of age and myelin ovoids and dark axons are seen (J:174587)
• increase of docosahexaenoic acid-containing phosphatidylcholine in the gray matter
• PAS+ granules start to be seen in the perinuclear space and proximal axons of the anterior horn cells at 15 weeks of age, are frequent at 56 weeks and result in swelling of axons, and by 100 weeks, proximal axons are showing severe degeneration
• by 55 weeks of age, axons throughout the central and peripheral nervous system exhibit spheroid swellings that measure 3-90 micrometers in diameter
• spheroids are most prominent in the tegmentum of the medulla, the lower pons and the dorsal horns of the spinal cord in mice over 1 year of age
• vacuoles are also detected throughout the nervous system with the greatest number of these occurring in the cerebral cortex in mice over 1 year of age
• in mice 15 weeks of age, tiny vacuoles are frequently observed in the molecular layer of the cerebellum and spheroids in the dentate nucleus of the cerebellum
• mutants exhibit progressive axonal degeneration in the distal parts of axons in the posterior horns of the lumbar cord and sciatic nerves that is severe by 100 weeks of age
• neuroaxonal dystrophy associated with insufficient remodeling of the mitochondrial inner membrane and presynaptic membrane of axon terminals
• progressive increase of spheroids in axons, such that by 100 weeks of age, large spheroids with or without PAS+ granules are seen in the spinal cord and in the posterior horns and axons in the anterior root

skeleton
• 2 year old mice have a hunched posture though X-ray analysis does not reveal any abnormalities in bone density or structure

cellular
• already at 15 weeks of age, mutants exhibit presence of abnormal mitochondria with degenerated inner membranes and mitochondria collapse in axons
• increase of cardiolipin suggests insufficient remodeling of mitochondrial inner membranes
• abnormal mitochondria with tubular and branching cristae are seen after 56 weeks of age

Mouse Models of Human Disease
OMIM IDRef(s)
Neurodegeneration with Brain Iron Accumulation 2A; NBIA2A 256600 J:174587