All Phenotypes Letm1<Gt(DD0926)Wtsi> MGI Mouse

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

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

• heterozygous intercrosses yield 52.7% 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)
Citing These Resources Funding Information Warranty Disclaimer, Privacy Notice, Licensing, & Copyright Send questions and comments to User Support.	last database update 11/19/2024 MGI 6.24