All Phenotypes Letm1<Gt(CC0204)Wtsi> MGI Mouse

embryonic lethality during organogenesis, incomplete penetrance ( J:222017 )

• ~50% of heterozygous embryos die before E13.5

• heterozygous intercrosses yield 53.6% of heterozygotes at birth

embryonic growth retardation ( J:222017 )

• E9.5 heterozygous embryos are growth-retarded

decreased embryo size ( J:222017 )

• at E9.5

abnormal embryo development ( J:222017 )

• decreased rate of DNA synthesis (BrdU incorporation) in E9.5 heterozygous embryos

• however, no significant increase in apoptosis at E9.5, as shown by TUNEL staining

• surviving E13.5 heterozygotes appear grossly normal

embryonic growth retardation ( J:222017 )

• E9.5 heterozygous embryos are growth-retarded

decreased embryo size ( J:222017 )

• at E9.5

abnormal mitochondrial physiology ( J:222017 )

• reduced mitochondrial Ca²⁺ (Ca²⁺ mito) uptake rates, low steady-state [Ca²⁺]mito, and decreased matrix pH in cultured primary fibroblasts derived from E13.5 heterozygous embryos relative to wild-type fibroblasts

• however, mitochondrial morphology and mitochondrial membrane potential are normal in heterozygous primary fibroblasts

• EM revaled no alterations in mitochondrial morphology in heterozygous tissues e.g. left ventricle area or hippocampus CA1 region

decreased oxygen consumption ( J:222017 )

• both basal and maximum oxygen consumption rates are reduced in heterozygous primary fibroblasts grown in low-glucose medium relative to wild-type fibroblasts

• however, oxygen consumption rates are normal in heterozygous fibroblasts grown in high-glucose media with pyruvate supplement

abnormal glucose homeostasis ( J:222017 )

• increases in key glycolysis intermediates are observed, consistent with a reduced mitochondrial ATP generation capacity

• reduced glucose, but not fatty acid, oxidation accounts for the differential impact of tissue [ATP]

• reduced glucose oxidation preferentially affects glucose-dependent tissues e.g. neurons and developing tissues

abnormal amino acid metabolism ( J:222017 )

• altered tryptophan metabolism in heterozygous brain tissue

abnormal enzyme/coenzyme activity ( J:222017 )

• activity of pyruvate dehydrogenase, the key rate-limiting Ca²⁺-sensitive enzyme that controls glucose oxidation, is significantly reduced in brain tissues after 48 h of fasting

increased susceptibility to pharmacologically induced seizures ( J:222017 )

• increased susceptibility to kainic acid-induced seizures with initial seizure scores being 1.5-fold higher than in wild-type controls at 45 min post-kainic acid injection, and total cumulative scores increasing ~25%

• brain, but not heart, [ATP] is reduced 25% after kainic acid treatment

abnormal brain morphology ( J:222017 )

• a 27% reduction in brain [ATP] is observed after 48 h of fasting at 6 weeks of age, whereas liver and heart [ATP] are not significantly altered

abnormal liver physiology ( J:222017 )

• significant reduction of beta-hydroxybutyrate levels in heterozygous liver samples under normal feeding conditions

increased susceptibility to pharmacologically induced seizures ( J:222017 )

• increased susceptibility to kainic acid-induced seizures with initial seizure scores being 1.5-fold higher than in wild-type controls at 45 min post-kainic acid injection, and total cumulative scores increasing ~25%

• brain, but not heart, [ATP] is reduced 25% after kainic acid treatment

decreased heart weight ( J:222017 )

• modestly decreased heart/body weight ratio under resting conditions at 6 weeks of age

craniofacial phenotype ( J:222017 )

N	• born heterozygotes appear grossly normal with no obvious facial or midline developmental defects at 6 weeks of age

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

Contributing Projects: Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
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