Mouse Genome Informatics
hm
    Cbstm1Unc/Cbstm1Unc
involves: 129P2/OlaHsd * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       

Abnormal hepatocyte morphology in Cbstm1Unc/Cbs+ and Cbstm1Unc/Cbstm1Unc mice

mortality/aging
• 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
• 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)

growth/size
• at P21, most homozygotes appear runted relative to wild-type mice (J:23321)
• 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)
• 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)

liver/biliary system
• 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
• 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
• 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
• occasionally, older female homozygotes (one 3-mo-old and one 6-mo-old) show hepatomegaly with subtle autolyic changes
• at P21, some mutant hepatocytes contain microvesicular cytoplasmic lipid droplets (J:23321)
• on a standard laboratory diet, homozygotes develop hepatic steatosis at ~P15, with lipid droplets containing triacylglycerols and cholesteryl esters (J:101303)
• 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 (J:101303)
• 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
• at P21, mutant livers show a light tan color instead of a normal reddish-brown color

homeostasis/metabolism
• 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 show a 20-fold increase in mean hepatic homocysteine levels relative to wild-type mice (J:101303)
• 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)
• at day 6 after mating with vasectomized males, plasma progesterone levels are significantly higher in pseudo-pregnant female homozygotes relative to their wild-type counterparts
• at P21, one of 4 homozygotes display hemosiderin deposits in spleen
• at 8- and 12 weeks, mutant livers display significantly higher IL-6 mRNA levels relative to wild-type livers
• 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

hematopoietic system
• at P21, mutant (but not wild-type) hepatocytes display extramedullary hematopoiesis

limbs/digits/tail
• 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
• homozygotes dying at early postnatal stages display tails and extremities of smaller diameters relative to their length

reproductive system
• at 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)
• 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 (J:114850)
• in addition, superovulated female homozygotes display an increased Oil red O staining of lipids in the ovarian corpora lutea relative to wild-type females (J:114850)
• 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 (J:114850)
• notably, the endometrium, muscular layer and perimetrium appear histologically normal (J:114850)
(J:114850)
(J:114850)
• infertile female homozygotes show a shorter and irregular estrus cycle (J:114850)
• both estrus and diestrus periods are decreased while the metestrus is prolonged (J:114850)
• 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 (J:114850)
• 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)
• 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 of homozygous mutant females (J:114850)
• 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)
• 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

vision/eye
• at P21, mutant eyes appear immature relative to wild-type or heterozygous eyes; however, no ocular pathology is observed
• at P21, most homozygotes exhibit smaller eyes
• homozygotes dying at early postnatal stages show delayed eyelid opening

respiratory system
• at P21, mutant lungs appear immature relative to wild-type or heterozygous lungs

renal/urinary system
• at P21, mutant kidneys appear immature relative to wild-type or heterozygous kidneys

cardiovascular system
• at P21, mutant hearts appear immature relative to wild-type or heterozygous hearts
• no thrombi are detected in vascular segments or other tissues

craniofacial
• homozygotes dying at early postnatal stages have faces that are typical of very young animals
• homozygotes display a pointed snout

endocrine/exocrine glands
• at 3 months, homozygotes exhibit hyperplastic sebaceous glands
• 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 (J:114850)
• in addition, superovulated female homozygotes display an increased Oil red O staining of lipids in the ovarian corpora lutea relative to wild-type females (J:114850)

cellular
• 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
• at 3 months, homozygotes exhibit accelerated maturation of keratinocytes
• at 3 months, the mutant epidermis displays enlarged spinous cells, in the absence of increased proliferation
• 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

immune system
• at 8- and 12 weeks, mutant livers display significantly higher IL-6 mRNA levels relative to wild-type livers
• 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
• 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

embryogenesis
• at 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)
• at day 18 of gestation, the junctional zone is reduced in placentae of female homozygotes
• at day 18 of gestation, the labyrinthine zone is enlarged in placentae of female homozygotes
• at day 18 of gestation, female homozygotes display a decrease of placental mass that correlates with the presence of weakened layers

integument
• at 3 months, homozygotes exhibit accelerated maturation of keratinocytes
• at 3 months, the mutant epidermis displays enlarged spinous cells, in the absence of increased proliferation
• at 3 months, homozygotes exhibit hyperplastic sebaceous glands
• homozygotes lack a normal healthy fur; in contrast, vibrissae, eyelids and nails appear normal
• 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
• at 3 months, mutant hair roots extend deeper into the subcutaneous fatty tissues while the basal portion of the follicles remains in the hypodermis
• homozygotes exhibit an increased number of hair follicles on their backs
• at 3 months, homozygotes display a thinner hypodermis
• at 3 months, homozygotes show a thin dermis; however, epidermal-dermal junctions appear normal
• at 3 months, homozygotes epidermal hyperkeratosis
• however, melanocyte morphology appears normal, and no changes in hair or skin color are observed

Mouse Models of Human Disease
OMIM IDRef(s)
Homocysteinemia 603174 J:23321
Homocystinuria Due to Cystathionine Beta-Synthase Deficiency 236200 J:105571