Phenotypes associated with this allele

• Allele Symbol: Col18a1^tm1Hms
• Allele Name: targeted mutation 1, Harvard Medical School
• Allele ID: MGI:2179134
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Col18a1^tm1Hms/Col18a1^tm1Hms	B6.129S4-Col18a1^tm1Hms	MGI:3046553
hm2	Col18a1^tm1Hms/Col18a1^tm1Hms	either: (involves: 129S4/SvJae * 129X1/SvJ) or (involves: 129S4/SvJae * C57BL/6J)	MGI:2664346
hm3	Col18a1^tm1Hms/Col18a1^tm1Hms	involves: 129S4/SvJae * C57BL/6J * C57BL/6JOlaHsd	MGI:5433684
cx4	Col18a1^tm1Hms/Col18a1^tm1Hms Hspg2^tm1Soin/Hspg2^tm1Soin	involves: C57BL/6 * C57BL/6J	MGI:3047564

Genotype
MGI:3046553

hm1

• Allelic Composition: Col18a1^tm1Hms/Col18a1^tm1Hms
• Genetic Background: B6.129S4-Col18a1^tm1Hms

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

homeostasis/metabolism

increased circulating triglyceride level ( J:167008 )

• fasting hypertriglyceridemia

increased circulating VLDL triglyceride level ( J:167008 )

abnormal enzyme/coenzyme level ( J:167008 )

• lipoprotein lipase is reduced on the luminal side of capillaries

abnormal circulating enzyme level ( J:167008 )

• plasma levels of lipoprotein lipase and are reduced

impaired lipolysis ( J:167008 )

• mutants exhibit delayed lipolysis of plasma triglycerides

renal/urinary system

renal/urinary system phenotype ( J:170560 )

N • distal tubular basement membranes are normal

podocyte foot process effacement ( J:170560 )

abnormal renal glomerulus morphology ( J:170560 )

• mice exhibit softening of kidney glomeruli compared with wild-type mice

abnormal proximal convoluted tubule morphology ( J:170560 )

• the proximal tubular basement membrane is broader than in wild-type mice

vision/eye

abnormal ciliary body morphology ( J:110852 )

• the nonpigmented ciliary body epithelium has less well-developed infoldings with a flattened morphology

• pigmented cell clusters and single cells cover the surface of the ciliary body, whereas no migration of these cells through the ciliary body is seen

abnormal iris morphology ( J:110852 )

• mice exhibit an age-dependent thickening of the anterior iris basement membrane zone which shows amorphous material and disorganized collagen fibrils

• abnormal migration of iris pigmented cells along the inner limiting membrane and penetration into the retina

• the iris-pupil area shows no typical iris ruff

abnormal iris pigment epithelium ( J:110852 )

• mice show variable separation within the iris pigment epithelium (IPE), with the posterior IPE cell layer commonly detached from the iris

• the detachment is often within the posterior IPE cell layer with rupture of the pigment cells and dispersed pigment granules

• the separated part of the posterior IPE layer adheres with its basement membrane to the posterior ciliary body basement membrane and to the lens

abnormal iris stromal pigmentation ( J:110852 )

• pigmented cell clusters and single cells cover the surface of the iris stroma

abnormal pupil morphology ( J:110852 )

• clusters or pigmented spots are seen in the pupil of 22 month old mice

abnormal cornea epithelium morphology ( J:110852 )

• pigmented spots cover the corneal endothelium

abnormal retina morphology ( J:110852 )

• aged mice show pigmented spots on the retinal surface consisting of pigmented cell clusters and single cells

• the pigmented cells appear as a string of cells, elongating from the iris along the retina and the optic nerve

• most of the pigmented cells are visible at the vitreous-retina border, however some are seen within the neural retina

• pigmented cells resemble iris clump cells and marker analysis indicates these as macrophage-like cells

abnormal retina vasculature morphology ( J:110852 )

• abnormal pattern of retinal vessels, with irregular bending of major retinal arteries

cardiovascular system

abnormal retina vasculature morphology ( J:110852 )

• abnormal pattern of retinal vessels, with irregular bending of major retinal arteries

pigmentation

abnormal iris pigment epithelium ( J:110852 )

• mice show variable separation within the iris pigment epithelium (IPE), with the posterior IPE cell layer commonly detached from the iris

• the detachment is often within the posterior IPE cell layer with rupture of the pigment cells and dispersed pigment granules

• the separated part of the posterior IPE layer adheres with its basement membrane to the posterior ciliary body basement membrane and to the lens

abnormal iris stromal pigmentation ( J:110852 )

• pigmented cell clusters and single cells cover the surface of the iris stroma

neoplasm

neoplasm ( J:75861 )

N • following inoculation with B16F10 melanoma and T241 fibrosarcoma tumor cells, homozygotes show no significant differences in the rate of growth of tumors over a period of 18 days relative to wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
pigment dispersion syndrome		DOID:0060680	OMIM:600510	J:110852

Genotype
MGI:2664346

hm2

• Allelic Composition: Col18a1^tm1Hms/Col18a1^tm1Hms
• Genetic Background: either: (involves: 129S4/SvJae * 129X1/SvJ) or (involves: 129S4/SvJae * C57BL/6J)

vision/eye

abnormal retina vasculature morphology ( J:75861 )

• at P4, homozygotes display delayed and variable outgrowth of retinal vessels, with 43.6% of mutant eyes showing no or only very few short vessels, 40% showing some but fewer vessels, and 16.4% showing normal vessel outgrowth

• among the 40% with some but fewer vessels, focal areas of abnormally dense capillary growth are detected in nearly half the samples

• abnormal retinal vascularization is associated with a ~50% reduction of VEGF expression levels in retinal neuroglia at P4

abnormal vitreous body morphology ( J:75861 )

• no collagen fibrils are observed in the periphery of the vitreous or in close proximity to the lamina densa of the inner limiting membrane of the retina, but the limiting membrane is otherwise normal

persistence of hyaloid vascular system ( J:75861 )

• unlike wild-type mice which display clear dissociation of the hyaloid vessels from the retinal surface along with the first signs of regression at P4, homozygotes exhibit a significant delay in postnatal regression of the hyaloid vessels along the inner limiting membrane of the retina

• mutant hyaloid capillaries are still present within the vitreous, near or attached to retina at P4 and P8, and persist even at P16, when wild-type hyaloid capillaries are completely removed from the vitreous

• at P4, P8, P16 and P24, homozygotes exhibit a significantly higher number of hyaloid vessels in the vitreous than wild-type mice

• at P8, the diameter of some mutant hyaloid capillaries is increased and numerous erythrocytes are observed

• whereas no hyaloid capillaries are found in wild-type mice at P24, a number of sections from mutant eyes exhibit numerous persistent and enlarged vessels in the vitreous

• in contrast, no differences are observed in the regression of vessels in the tunica vasculosa lentis

cardiovascular system

abnormal retina vasculature morphology ( J:75861 )

• at P4, homozygotes display delayed and variable outgrowth of retinal vessels, with 43.6% of mutant eyes showing no or only very few short vessels, 40% showing some but fewer vessels, and 16.4% showing normal vessel outgrowth

• among the 40% with some but fewer vessels, focal areas of abnormally dense capillary growth are detected in nearly half the samples

• abnormal retinal vascularization is associated with a ~50% reduction of VEGF expression levels in retinal neuroglia at P4

cellular

abnormal basement membrane morphology ( J:75861 )

• homozygotes exhibit significantly reduced numbers of vitreous collagen fibrils along the inner limiting membrane at the vitreous/retina interphase

Genotype
MGI:5433684

hm3

• Allelic Composition: Col18a1^tm1Hms/Col18a1^tm1Hms
• Genetic Background: involves: 129S4/SvJae * C57BL/6J * C57BL/6JOlaHsd

nervous system

subarachnoid hemorrhage ( J:92842 )

• massive subarachnoid bleeding in mice with severe hydrocephalus, likely secondary to pathologically increased intracranial pressure

abnormal brain morphology ( J:92842 )

• contraction of brain structures due to extensive dilation of the lateral ventricle and pathologically increased intracranial pressure in mice with severe hydrocephalus

abnormal brain ependyma motile cilium morphology ( J:92842 )

• the cilia of the ependymal cell layer are atrophic in mice with severe hydrocephalus

hydrocephaly ( J:92842 )

• ~20% of homozygotes develop severe hydrocephalus

enlarged brain ventricles ( J:92842 )

• significantly enlarged brain ventricles observed in all mice at the age of 3 weeks to 2 months, as shown by MRI

dilated fourth ventricle ( J:92842 )

• mild to severe dilation of the fourth ventricle at 3 weeks of age

dilated lateral ventricle ( J:92842 )

• mild to severe dilation of the lateral ventricles at 3 weeks of age

abnormal choroid plexus morphology ( J:92842 )

• choroid plexus (CP) epithelial cells are balloon-shaped rather than cuboidal, with individual cells forming protrusions into the ventricle

• instead of being apical, tight junctions are located closer to the basal side of CP epithelial cells

• CP epithelial cells show increased vacuolization, suggesting alterations in the CSF outflow

• apical microvilli (cilia) are abnormally dilated and contain numerous vacuoles

• the CP epithelium is ruptured in mice with severe hydrocephalus

dilated third ventricle ( J:92842 )

• mild to severe dilation of the third ventricle at 3 weeks of age

craniofacial

abnormal cranium morphology ( J:92842 )

• displaced skull bones in mice with severe hydrocephalus

enlarged cranium ( J:92842 )

• significantly enlarged skull in mice with severe hydrocephalus

renal/urinary system

abnormal mesangial matrix morphology ( J:92842 )

• mesangial matrix structure is altered from clearly defined to somewhat indefinite

expanded mesangial matrix ( J:92842 )

• mesangial matrix is increased in some glomeruli

• however, type IV collagen staining did not reveal increased immunosignal in glomeruli

abnormal proximal convoluted tubule morphology ( J:92842 )

• the proximal tubular BM is significantly broader and varies significantly in thickness both at 2 months and at 7-11 months of age

• in contrast, the BMs of the Bowman's capsule and the glomerulus remain structurally normal

cardiovascular system

abnormal tricuspid valve cusp morphology ( J:92842 )

• in cardiac tricuspid valve leaflets, the BM underlying the endothelial cell layer is significantly broader on both the atrial and ventricular sides, and both BMs vary significantly in thickness

subarachnoid hemorrhage ( J:92842 )

• massive subarachnoid bleeding in mice with severe hydrocephalus, likely secondary to pathologically increased intracranial pressure

homeostasis/metabolism

increased circulating creatinine level ( J:92842 )

• significantly increased serum creatinine levels relative wild-type controls

skeleton

abnormal cranium morphology ( J:92842 )

• displaced skull bones in mice with severe hydrocephalus

enlarged cranium ( J:92842 )

• significantly enlarged skull in mice with severe hydrocephalus

cellular

abnormal brain ependyma motile cilium morphology ( J:92842 )

• the cilia of the ependymal cell layer are atrophic in mice with severe hydrocephalus

abnormal basement membrane morphology ( J:92842 )

• in brain, the epithelial BM of the choroid plexus is significantly broader and varies significantly in thickness (at 2 months, ~86 nm relative to ~61 nm in wild-type mice)

• in skin, the epidermal BM is significantly broader and varies significantly in thickness (1.4-fold wider at 7-15 months)

• in cardiac tricuspid valve leaflets, the BM underlying the endothelial cell layer is significantly broader on both the atrial and ventricular sides , and both BMs vary significantly in thickness (>2-fold wider at 2 months)

• in kidney, the proximal tubular BM is significantly broader and varies significantly in thickness both at 2 months and at 7-11 months of age

Genotype
MGI:3047564

cx4

• Allelic Composition: Col18a1^tm1Hms/Col18a1^tm1Hms; Hspg2^tm1Soin/Hspg2^tm1Soin
• Genetic Background: involves: C57BL/6 * C57BL/6J

vision/eye

abnormal lens development ( J:81399 )

• double mutant newborns display accelerated lens degeneration relative to Hspg2^tm1Soin mice, as well as more severe lens defects relative to single mutant mice

• the first signs of abnormal development are already apparent in neonates in that leakages of cells are detected in the anterior region of the lens; in Hspg2^tm1Soin mice, leakages are observed in a more posterior region and are less severe

• in double mutant lenses, epithelial cells migrate focally outwards, proliferate and remain external for several weeks