Mouse Genome Informatics
hm
    Sc5dtm1Fdp/Sc5dtm1Fdp
involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• homozygous mutant pups are stillborn, though cardiac activity is detected just prior to birth

growth/size/body
• 88% of neonatal mutant pups display a cleft palate, not observed in wild-type pups
• mutant pups display a narrow frontonasal process
• mutant pups have an average birth weight of 1.10 0 .01 g relative to 1.38 0.12 for control pups
• mutant pups are growth retarded at birth, indicating a delay in intrauterine growth

craniofacial
• mutant pups display calvarial defects
• the mineralized part of the interparietal bone is hypoplastic
• mutant pups display hypoplasia of the distal mandibular arch
• all mutant pups exhibit micrognathia due to hypoplasia of the distal mandidublar arch
• 88% of neonatal mutant pups display a cleft palate, not observed in wild-type pups
• mutant pups display a narrow frontonasal process

limbs/digits/tail
• mutant pups display autopod patterning defects
• mutant pups show a variable bifurcation of the fourth medial phalanges of either the fore or hind limbs
• bifurcation of the fourth medial phalanges is noted in at least one limb, in 56% of mutant embryos but in none of 10 control embryos
• proximal phalangeal bones display a more rectangular shape while middle phalangeal bones appear hypoplastic
• 32% of mutant pups display postaxial polydactyly of the forelimbs versus only 5% of littermate controls
• mutant pups exhibit bowed tibia and fibia
• mutant pups display limb patterning defects in both the proximal-distal as well as the preaxial-postaxial axes
• mutant pups exhibit short and malformed fore- and hind limbs
• most mutant pups have kinked tails

homeostasis/metabolism
• mutant pups exhibit subcutaneous edema
• mutant pups display a reduced glycogen level in the liver
• at E18.5, mutant embryos exhibit significantly increased tissue and serum levels of lathosterol relative to wild-type or heterozygous embryos
• in mutant tissues lathosterol accounts for 39% (serum), 48% (cortex), 53% (midbrain), 62% (liver), 52% (kidney) or 55% (skeletal muscle) of total sterols, whereas in wild-type tissues lathosterol accounts for 0.1-1.1% of total sterols, with the highest fractions in cortex (0.9%) and midbrain (1.1%)
• in mutant liver tissue the fraction of lathosterol increases from 32% at E12.5 to 61% at E18.5 with a corresponding reduction in cholesterol levels
• in mutant brain tissue increased lathosterol and significantly decreased cholesterol levels are noted from E12.5 to E18.5
• in E18.5 mutant cortex tissue desmosterol levels are significantly decreased, along with a 35-fold increase in cholesta-7,24-diene-3beta-ol and a 63-fold accumulation of lathosterol
• at E18.5, mutant embryos display significantly decreased tissue and serum cholesterol levels relative to wild-type or heterozygous embryos
• in older mutant embryos, reduced cholesterol levels probably represent a dilution of maternally-derived cholesterol from the yolk sac as endogenous synthesis leads to lathosterol accumulation
• in mutant brain tissue significantly decreased cholesterol levels are noted from E12.5 to E18.5

skeleton
• mutant pups display calvarial defects
• the mineralized part of the interparietal bone is hypoplastic
• mutant pups display hypoplasia of the distal mandibular arch
• all mutant pups exhibit micrognathia due to hypoplasia of the distal mandidublar arch
• mutant pups show a variable bifurcation of the fourth medial phalanges of either the fore or hind limbs
• bifurcation of the fourth medial phalanges is noted in at least one limb, in 56% of mutant embryos but in none of 10 control embryos
• proximal phalangeal bones display a more rectangular shape while middle phalangeal bones appear hypoplastic
• mutant pups exhibit bowed tibia and fibia
• most mutant pups have gracile ribs

digestive/alimentary system
• 88% of neonatal mutant pups display a cleft palate, not observed in wild-type pups
• mutant pups display decreased zymogen granules in the pancreas

respiratory system
• mutant pups display a narrow frontonasal process
• mutant pups display diffuse atelectasis in the lung

adipose tissue
• mutant pups show increased vacuolation in brown fat tissue

endocrine/exocrine glands
• mutant pups display decreased zymogen granules in the pancreas

liver/biliary system
• in mutant pups, liver size is relatively increased (7% of body weight compared with 4% in controls) in the absence of overt lysosomal accumulation in either liver or brain tissue

cellular
• when mutant mouse embryonic fibroblasts are grown in cholesterol deficient media, enlarged membrane-bound cytoplasmic vacuoles with lamellar inclusions are observed; these intracellular inclusions appear to be in lysosomes and are not found in control cell lines

integument
• mutant pups exhibit subcutaneous edema

nervous system
• in mutant brain tissue significantly decreased cholesterol levels are noted from E12.5 to E18.5

Mouse Models of Human Disease
OMIM IDRef(s)
Lathosterolosis 607330 J:84450