Analysis Tools
mortality/aging
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• on a standard laboratory diet, homozygotes show a high incidence of lethality between 3 and 4 weeks after birth, with the majority dying within 5 weeks of age; only ~20% of the expected number is obtained at 5-12 weeks of age
(J:23321)
• dietary supplementation with choline at weaning extends postnatal survival to adulthood
(J:105571)
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• homozygotes are present at roughly the expected Mendelian frequency until P14; however, less than 60% of the expected number of homozygotes are obtained at 3 weeks of age
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growth/size/body
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• homozygotes dying at early postnatal stages have faces that are typical of very young animals
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• homozygotes display a pointed snout
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• at P21, most homozygotes appear runted relative to wild-type mice
(J:23321)
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• at P14, homozygotes display body weights that are only 80% of those found in wild-type or heterozygous mice
(J:23321)
• at 3 weeks, homozygotes weigh significantly less than wild-type mice
(J:105571)
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• homozygotes show a progressive failure in weight gain after P7; differences in body weight become pronounced between P14 and P21
(J:23321)
• a few homozygotes surviving >2 months display normal stature at weaning and maintain a relatively normal body size until just before death
(J:23321)
• on a choline-enriched diet, adult homozygotes exhibit growth retardation, weighing an average of 20% less than wild-type or heterozygous mice
(J:105571)
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• occasionally, older female homozygotes (one 3-mo-old and one 6-mo-old) show hepatomegaly with subtle autolyic changes
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liver/biliary system
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• at 8- and 12 weeks, mutant livers exhibit a significantly increased proapoptotic Bax/Bcl-2 ratio (up to 16 vs. 1 arbitrary unit), suggesting induction of a mitochondrial apoptotic pathway
• however, no caspase-3 activation, DNA fragmentation, or TUNEL-positive cells are detected at 12 weeks or later, suggesting that protective signals may counteract apoptotic signals, leading to chronic inflammation
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• occasionally, older female homozygotes (one 3-mo-old and one 6-mo-old) show hepatomegaly with subtle autolyic changes
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• on a choline-enriched diet, 8-week-old and ageing homozygotes display mild hepatic inflammation, with foci of perilobular mononuclear inflammatory infiltrates around the vessels
• however, no hepatocyte necrosis is detected up to 32 weeks age
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• at P14-P21, mutant hepatocytes appear enlarged and pleiomorphic, with a 2-fold increase in mean diameter and enlarged nuclei; multi- and binucleated hepatocytes are present
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• on a standard laboratory diet, homozygotes develop hepatic steatosis at ~P15, with lipid droplets containing triacylglycerols and cholesteryl esters
• on a choline-enriched diet, homozygotes exhibit a mild, localized hepatic steatosis (grade 1) at 12 and 18 weeks, which progresses to extensive grade 2 steatosis by 32 weeks of age
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• at P21, some mutant hepatocytes contain microvesicular cytoplasmic lipid droplets
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• on a standard laboratory diet, homozygotes develop hepatic fibrosis at ~P15
• on a choline-enriched diet, 8-week-old homozygotes display a mild hepatic perivascular fibrosis which progresses to pericellular fibrosis at week 12 and portal fibrosis by week 32, along with a ~50-fold increase in liver collagen content
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pale liver
(
J:23321
)
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• at P21, mutant livers show a light tan color instead of a normal reddish-brown color
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homeostasis/metabolism
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• at 3 months, homozygotes show a 20-fold increase in mean hepatic homocysteine levels relative to wild-type mice
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• at P21, F2 homozygotes show plasma homocysteine levels that are ~40 times higher than those of age-matched wild-type mice
(J:23321)
• at 3 months, homozygotes fed a choline-enriched diet, show a 50-fold increase in total plasma homocysteine levels relative to similarly fed wild-type mice
(J:105571)
• pregnant females show a significant increase in total plasma homocysteine levels from day 4 to day 16 of gestation
(J:190486)
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• on day 6 after mating with vasectomized males, plasma progesterone levels are significantly higher in pseudo-pregnant female homozygotes relative to their wild-type counterparts
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hemosiderosis
(
J:23321
)
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• at P21, one of 4 homozygotes display hemosiderin deposits in spleen
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• on day 8 of gestation, a significant increase in protein levels of alpha-fetoprotein is detected in decidual cells
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• at 8- and 12 weeks, mutant livers display significantly higher IL-6 mRNA levels relative to wild-type livers
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• at 8- and 12 weeks, mutant livers display significantly higher TNF mRNA levels relative to wild-type livers; CD14 mRNA levels are also increased, confirming Kuppfer cell activation and elevated TNF production
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hematopoietic system
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• on day 8 of gestation, a significant decrease in uterine NK cells expressing granzyme b is observed in the decidua basalis
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• no uterine NK cells are histologically detected on day 12 of gestation; instead, implantation sites are filled with connective tissue
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• at P21, mutant (but not wild-type) hepatocytes display extramedullary hematopoiesis
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limbs/digits/tail
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• homozygotes dying at early postnatal stages display tails and extremities of smaller diameters relative to their length
• at P21, mutant knee joints appear immature relative to wild-type joints
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• homozygotes dying at early postnatal stages display tails and extremities of smaller diameters relative to their length
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reproductive system
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• on day 12 of gestation, no consolidation of decidua is observed, unlike in wild-type pregnant females; instead, tissue degeneration is accompanied by necrosis
(J:190486)
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• on day 18 of gestation, the thickness of decidual layer is reduced in placentas from pregnant female homozygotes, indicating reduced trophoblast invasion in these females
(J:114850)
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• on day 8 of gestation, a significant decrease in uterine NK cells expressing granzyme b is observed in the decidua basalis
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• no uterine NK cells are histologically detected on day 12 of gestation; instead, implantation sites are filled with connective tissue
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• in response to the ovulatory surge of hCG, female homozygotes develop less follicles than wild-type females, indicating a reduced response to pregnant mare serum gonadotropin
• in addition, superovulated female homozygotes display an increased Oil red O staining of lipids in the ovarian corpora lutea relative to wild-type females
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• female homozygotes show a striking decrease in gravid uterine weight relative to wild-type females; this is accompanied by significant reductions in placental and fetal weights
• notably, the endometrium, muscular layer and perimetrium appear histologically normal
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short estrus
(
J:114850
)
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• infertile female homozygotes show a shorter and irregular estrus cycle
• both estrus and diestrus periods are decreased while the metestrus is prolonged
• differences in estrus cycle have no effect over the number of oocytes ovulated during normal estruses, although the yield is much lower when female homozygotes are superovulated
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• when 90-day-old female homozygotes are mated with homologous male partners, pregnancy loss occurs between day 8 and day 12 of gestation (during placenta formation), with significant decreases in the mass of dissected uteri and embryos from day 8 to day 16
(J:190486)
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• despite a similar number of implantation sites, the percentage of surviving fetuses in homozygous pregnant females is severely reduced relative to wild-type pregnant females
(J:114850)
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• as both mutant ovaries and ovulated oocytes appear morphologically normal, authors suggest that uterine dysfunction is a consequence of either hyperhomocysteinemia or other factor(s) in the uterine environment
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• transcriptomic analyses of implantation and interimplantation sites showed impaired decidualization and altered gene expression networks in the uterus on day 8 of gestation
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• female homozygotes surviving >2months fail to reproduce
(J:23321)
• female homozygotes show normal sexual behavior but are infertile due to uterine failure
(J:114850)
• fertility is restored when homozygous mutant ovaries are transplanted to normal ovarectomized recipients
(J:114850)
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• matings between female x male homozygotes result in a drastic reduction of litter size, since five homozygous females had only two born pups, which died soon after birth, versus 39 obtained with heterozygous females
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vision/eye
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• at P21, mutant eyes appear immature relative to wild-type or heterozygous eyes; however, no ocular pathology is observed
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• at P21, most homozygotes exhibit smaller eyes
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• homozygotes dying at early postnatal stages show delayed eyelid opening
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respiratory system
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• at P21, mutant lungs appear immature relative to wild-type or heterozygous lungs
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renal/urinary system
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• at P21, mutant kidneys appear immature relative to wild-type or heterozygous kidneys
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cardiovascular system
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• at P21, mutant hearts appear immature relative to wild-type or heterozygous hearts
• no thrombi are detected in vascular segments or other tissues
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craniofacial
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• homozygotes dying at early postnatal stages have faces that are typical of very young animals
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• homozygotes display a pointed snout
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endocrine/exocrine glands
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• on day 8 of gestation, a significant decrease in uterine NK cells expressing granzyme b is observed in the decidua basalis
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• no uterine NK cells are histologically detected on day 12 of gestation; instead, implantation sites are filled with connective tissue
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• at 3 months, homozygotes exhibit hyperplastic sebaceous glands
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• in response to the ovulatory surge of hCG, female homozygotes develop less follicles than wild-type females, indicating a reduced response to pregnant mare serum gonadotropin
• in addition, superovulated female homozygotes display an increased Oil red O staining of lipids in the ovarian corpora lutea relative to wild-type females
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cellular
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• at 8- and 12 weeks, mutant livers exhibit a significantly increased proapoptotic Bax/Bcl-2 ratio (up to 16 vs. 1 arbitrary unit), suggesting induction of a mitochondrial apoptotic pathway
• however, no caspase-3 activation, DNA fragmentation, or TUNEL-positive cells are detected at 12 weeks or later, suggesting that protective signals may counteract apoptotic signals, leading to chronic inflammation
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• at 3 months, homozygotes exhibit accelerated maturation of keratinocytes
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• at 3 months, mutant livers exhibit enhanced protein oxidation and lipid peroxidation, as shown by a ~30% increase in oxidatively modified proteins (carbonyls) and a similar increase in MDA and 4-HNE aldehydes, respectively
• hepatic oxidative stress may cause mitochondrial damage in association with activation of hepatic Kuppfer (stellate) cells, leading to liver injury
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immune system
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• on day 8 of gestation, a significant decrease in uterine NK cells expressing granzyme b is observed in the decidua basalis
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• no uterine NK cells are histologically detected on day 12 of gestation; instead, implantation sites are filled with connective tissue
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• at 8- and 12 weeks, mutant livers display significantly higher IL-6 mRNA levels relative to wild-type livers
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• at 8- and 12 weeks, mutant livers display significantly higher TNF mRNA levels relative to wild-type livers; CD14 mRNA levels are also increased, confirming Kuppfer cell activation and elevated TNF production
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• on a choline-enriched diet, 8-week-old and ageing homozygotes display mild hepatic inflammation, with foci of perilobular mononuclear inflammatory infiltrates around the vessels
• however, no hepatocyte necrosis is detected up to 32 weeks age
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embryo
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• on day 12 of gestation, no consolidation of decidua is observed, unlike in wild-type pregnant females; instead, tissue degeneration is accompanied by necrosis
(J:190486)
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• on day 18 of gestation, the thickness of decidual layer is reduced in placentas from pregnant female homozygotes, indicating reduced trophoblast invasion in these females
(J:114850)
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• on day 8 of gestation, a significant decrease in uterine NK cells expressing granzyme b is observed in the decidua basalis
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• no uterine NK cells are histologically detected on day 12 of gestation; instead, implantation sites are filled with connective tissue
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• on day 18 of gestation, the junctional zone is reduced in placentae of female homozygotes
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• on day 18 of gestation, the labyrinthine zone is enlarged in placentae of female homozygotes
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• on day 18 of gestation, female homozygotes display a decrease of placental mass that correlates with the presence of weakened layers
(J:114850)
• placental weight is significantly decreased on day 12 of gestation
(J:190486)
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• transcriptomic analyses of implantation and interimplantation sites showed impaired decidualization and altered gene expression networks in the uterus on day 8 of gestation
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integument
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• at 3 months, homozygotes exhibit accelerated maturation of keratinocytes
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• at 3 months, homozygotes exhibit hyperplastic sebaceous glands
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• homozygotes lack a normal healthy fur; in contrast, vibrissae, eyelids and nails appear normal
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• at 3 months, homozygotes exhibit a sparse fur on their head and a more dense fur on their backs
• homozygotes display a variable reduction in the (mid-shaft) diameter of back, abdominal, and head hairs
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• at 3 months, homozygotes display a thinner hypodermis
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• at 3 months, mutant hair roots extend deeper into the subcutaneous fatty tissues while the basal portion of the follicles remains in the hypodermis
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• homozygotes exhibit an increased number of hair follicles on their backs
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• at 3 months, homozygotes show a thin dermis; however, epidermal-dermal junctions appear normal
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• at 3 months, homozygotes epidermal hyperkeratosis
• however, melanocyte morphology appears normal, and no changes in hair or skin color are observed
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• at 3 months, the mutant epidermis displays enlarged spinous cells, in the absence of increased proliferation
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| homocystinuria | DOID:9263 |
OMIM:236200 OMIM:236250 |
J:105571 | |
