Phenotypes Associated with This Genotype

Genotype
MGI:3047689

• Allelic Composition: Lum^tm1Chak/Lum^tm1Chak
• Genetic Background: involves: 129S/Sv * CD-1

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

cardiovascular system

cardiovascular system phenotype ( J:48068 )

N • homozygotes display no major cardiac valvular defects

bruising ( J:48068 )

• homozygotes bruise easily

cellular

abnormal apoptosis ( J:89489 )

• at P10, homozygous mutant mice exhibit increased proliferation and decreased apoptosis of stromal keratocytes during postnatal maturation of the cornea

• in addition, 6-week-old homozygotes show a significant reduction in apoptosis during stromal wound healing

decreased fibroblast apoptosis ( J:89489 )

• mutant MEFs display reduced apoptosis relative to wild-type

increased fibroblast proliferation ( J:89489 )

• in culture, mutant corneal fibroblasts show increased growth relative to wild-type

• mutant mouse embryonic fibroblasts (MEFs) display increased rates of proliferation relative to wild-type

digestive/alimentary system

digestive/alimentary phenotype ( J:48068 )

N • homozygotes display no major gastrointestinal tract defects

growth/size/body

decreased body size ( J:48068 )

• homozygotes are viable and fertile; however, ~10-15% of mutant mice are significantly smaller at birth

decreased body weight ( J:48068 )

• homozygotes weigh 70-80% of the body weight of wild-type littermates

muscle

abnormal tendon morphology ( J:65867 )

• at P4, mutant tendons show a shift in the relatively homogeneous collagen fibril diameter distributions to larger diameters (72-nm versus 64-nm in wild-type)

• at P10, mutant tendons have relatively equal numbers of fibrils with intermediate diameters (between 65- and 140-nm)

• at 1-3 months, mutant tendons display only slight alterations in collagen fibril diameter relative to wild-type; no differences are detected thereafter

skeleton

abnormal tendon morphology ( J:65867 )

• at P4, mutant tendons show a shift in the relatively homogeneous collagen fibril diameter distributions to larger diameters (72-nm versus 64-nm in wild-type)

• at P10, mutant tendons have relatively equal numbers of fibrils with intermediate diameters (between 65- and 140-nm)

• at 1-3 months, mutant tendons display only slight alterations in collagen fibril diameter relative to wild-type; no differences are detected thereafter

vision/eye

abnormal cornea morphology ( J:48068 , J:70246 )

• mutant corneas display abnormal arrangement of collagen fibrils and keratinocytes (J:48068)

• TEM revealed that mutant corneal collagen fibrils show a wide range of fiber diameter (i.e. thicker fibrils in addition to fibrils of normal diameter), shape irregularities due to lateral fusions, and increased and non-uniform interfibrillar spacing (J:48068)

• X-ray diffraction patterns from mutant corneas revealed abnormally diffuse interfibrillar reflections (J:70246)

• at 6 months, the average collagen fibril spacing is marginally higher (~7%) in mutant corneas relative to wild-type (J:70246)

• at both 2- and 6-months, X-ray patterns from mutant corneas fail to register any measurable subsidiary X-ray reflection, indicating a broader than normal range of fibril diameters (J:70246)

abnormal cornea stroma morphology ( J:48068 , J:64730 )

• beginning at 5 weeks, the mutant stroma appears uniformly hazy and opalescent (J:48068)

• the entire mutant stroma appears bright due to increased backscattered light (J:64730)

decreased cornea stroma thickness ( J:64730 , J:81616 )

• at 4-5 months of age, homozygotes display a 40% reduction in stromal thickness (J:64730)

• at this age, mutant mice also show a 12% reduction in epithelial thickness (J:64730)

• in contrast to wild-type, mutant stroma never increases in thickness from week 1 to 2, remains markedly thinner at 2 weeks, and becomes significantly thinner from week 2 to week 3 after eyelid opening (J:81616)

abnormal cornea posterior stroma morphology ( J:64730 )

• the posterior stroma contains numerous large-diameter collagen fibrils, many with irregular contours, indicating abnormal lateral growth

• also, the posterior stroma displays abnormally large fibril aggregates, aberrant fibril packing, and impaired lamellar organization

• notably, the anterior stroma appears relatively unaffected

abnormal cornea stroma development ( J:48068 , J:81616 )

• homozygotes display normal development of the corneal stroma between E13.5 and E16.5 (J:48068)

• in contrast to wild-type corneal stroma, mutant stroma fails to undergo swelling from P8 to P12 (eyelid opening stage), followed by thinning at P14 (J:81616)

cornea opacity ( J:48068 , J:64730 )

• at 5 to 34 weeks, 44 out of 51 homozygotes show bilateral corneal clouding with a peripheral ring-like clear zone (J:48068)

• corneal opacity is age-dependent: by 8-12 weeks, most homozygotes have cloudy corneas (J:48068)

• also, corneal clouding is progressive: all homozygotes show an increase in opacity over time (J:48068)

• importantly, no mutants exhibit total opacification where iris details are undetectable (J:48068)

• whole eyes from mutant mice exhibit a 25% reduction in total ocular keratan sulfate levels, contributing to reduced corneal transparency (J:64730)

sclera thinning ( J:83544 )

• homozygotes show a significant reduction in posterior sclera thickness and a decrease in the number of lamellae

• mutant scleras display lamellar disorganization and occasional fibril-poor areas

• in the sclera, the range and distribution of collagen fibril diameter is not severely affected

increased corneal light-scattering ( J:64730 , J:81616 )

• on average, homozygotes show a 3-fold increase in backscattering of light, with maximal increase restricted to the posterior stroma (J:64730)

• corneas from wild-type neonates show a rapid loss of light-scattering, decreasing by 50% from P1 to P12 (eyelid opening), concomittant with a 60% decrease in keratocyte density (J:81616)

• in contrast, corneas from mutant neonates show a significant increase in light-scattering at 3 weeks, when stroma thickness is reduced significantly (J:81616)

• in mutant posterior corneas, light-scattering is diffuse as opposed to granular, and remains elevated above wild-type levels, in the absence of significant changes in keratocyte proliferation or differentiation (J:81616)

integument

abnormal dermal layer morphology ( J:48068 )

• homozygotes display a disorganized and loosely arranged dermal connective tissue

• mutant dermal fibroblasts appear disoriented relative to wild-type

• in tail preparations (skin and tendon), dermal regions show increased interfibrillar spacing and a wide range of fiber diameter

• tail skin collagen fibrils are less affected relative to corneal collagen fibrils

loose skin ( J:48068 )

• homozygotes exhibit skin laxity and fragility

skin lesions ( J:48068 )

• homozygotes display an increased incidence of skin lesions

decreased skin tensile strength ( J:48068 )

• homozygotes display an 86% reduction in skin tensile strength relative to wild-type

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Ehlers-Danlos syndrome classic type 1		DOID:14720	OMIM:130000	J:48068