All Phenotypes Agpat1<tm1Garg> MGI Mouse

premature death ( J:250301 )

• among mice surviving past P21, only ~10% reach sexual maturity at 6 weeks of age

• few mice live beyond 10 weeks of age despite efforts to rescue them with food or glucocorticoids

postnatal lethality, incomplete penetrance ( J:250301 )

• mice exhibit major neonatal death between P0 and P21; ~50% of mice do not survive beyond 3 to 4 weeks

• treatment with daily i.p. injections of dexamethasone, peanut oil, or a soft diet starting at P10 fails to improve survival

decreased body weight ( J:250301 )

• both sexes show significantly reduced body weight by P12

slow postnatal weight gain ( J:250301 )

• mice fail to gain weight after weaning; only two mice (one male and one female) reached proper weight to undergo metabolic cage experiments

abnormal epididymal fat pad morphology ( J:250301 )

• at P21, epididymal white adipose tissue (eWAT) is visibly reduced; however, tissue was too small to weigh reliably

decreased percent body fat/body weight ( J:250301 )

• mice show reduced but not absent total body fat when normalized to total body weight by P21 (~66% decrease for males and 69% decrease for females)

• however, no generalized lipodystrophy is observed

homeostasis/metabolism phenotype ( J:250301 )

N

• mice show no significant differences in O₂ consumption, CO₂ production, respiratory exchange ratio, or energy expenditure relative to wild-type controls

• plasma insulin and glucagon levels are normal in both sexes

• male plasma testosterone levels are normal

• female plasma FSH, estradiol, and progesterone levels are normal

decreased circulating glucose level ( J:250301 )

• at P12 to P19, mice exhibit a significant decrease in plasma glucose levels by tail vein puncture relative to wild-type controls

• mice surviving to P21 show a significantly lower plasma glucose level obtained by cardiac puncture than wild-type controls

• exogenous daily administration of glucose starting at P10 does not improve survivability

hypoglycemia ( J:250301 )

increased circulating follicle stimulating hormone level ( J:250301 )

• at 6 weeks of age, males have significantly higher plasma FSH levels than wild-type controls

increased circulating luteinizing hormone level ( J:250301 )

• at 6 weeks of age, males have significantly higher plasma LH levels than wild-type controls

decreased circulating insulin-like growth factor I level ( J:250301 )

• plasma IGF-1 levels are decreased in both sexes consistent with downregulation of liver Igf-1 mRNA expression

decreased circulating leptin level ( J:250301 )

• both sexes show reduced plasma leptin levels at P21

impaired gluconeogenesis ( J:250301 )

• mice exhibit a decrease in the expression of enzymes involved in liver gluconeogenesis as well as transcriptional suppression of Foxo1, resulting in low plasma glucose levels

abnormal enzyme/coenzyme activity ( J:250301 , J:250301 )

	• whereas no significant decrease in total AGPAT (acyltransferase) enzymatic activity is observed in liver homogenates of male mice using either C15:0-CoA or C18:1-CoA substrates, a modest but significant decrease in total AGPAT activity is seen in liver homogenates of female mice with both substrates (J:250301)
	• total AGPAT enzymatic activity is significantly decreased in testis homogenates of male mice using C15:0-CoA relative to that in wild-type controls (J:250301)

behavior/neurological phenotype ( J:250301 )

N	• mice show no significant differences in food intake or water intake relative to wild-type controls

increased vertical activity ( J:250301 )

• only at nighttime

increased locomotor activity ( J:250301 )

• mice show significantly greater locomotor activity than wild-type controls (horizontal: 97% to 131%; vertical: 141% to 392%) only at nighttime

audiogenic seizures ( J:250301 )

• 7 of 11 mice develop behavioral seizure activity when subjected to a 100-dB audiogenic startle stimulus for 1 min versus only 3 of 15 similarly treated wild-type controls

• audiogenic responders show typical behaviors with wild running and jumping followed by loss of balance and tonic-clonic activity of the forelimbs and hind limbs

increased tertiary ovarian follicle number ( J:250301 )

• ovaries show a dramatic increase in the number of antral follicles

abnormal spermatogenesis ( J:250301 )

• spermatogenesis is disrupted at 6 weeks of age; spermatogenic cells develop into pachynema of meiotic prophase I but are unable to develop into round spermatids

abnormal spermatid morphology ( J:250301 )

• co-labeling with Hoechst 33342 nuclear dye and CREM or gammaH2AX revealed that no round or elongating spermatids are present in the seminiferous tubules at 6 weeks of age

abnormal spermatocyte morphology ( J:250301 )

• ~5% of seminiferous tubules completely lack gammaH2AX+ spermatocytes at 6 weeks of age

arrest of male meiosis ( J:250301 )

• males show a late meiotic arrest at steps between mid- to late-pachytene spermatocyte and round spermatid production

decreased ovulation rate ( J:250301 )

• female mice exhibit oligoanovulation; ovulatory defect is primarily central and most likely related to low body fat and leptin deficiency

• however, ovaries show normal responsiveness to human chorionic gonadotropin (hCG) stimulation

abnormal estrous cycle ( J:250301 )

• females show erratic erratic estrus cycles

prolonged diestrus ( J:250301 )

• most females tend to have prolonged diestrus stages

female infertility ( J:250301 )

male infertility ( J:250301 )