Phenotypes associated with this allele

• Allele Symbol: Lum^tm1Chak
• Allele Name: targeted mutation 1, Shukti Chakravarti
• Allele ID: MGI:2153008
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Lum^tm1Chak/Lum^tm1Chak	involves: 129S/Sv * CD-1	MGI:3047689
cx2	Fmod^tm1Aol/Fmod^tm1Aol Lum^tm1Chak/Lum^tm1Chak	involves: 129S1/Sv * 129X1/SvJ * CD-1	MGI:3047839
cx3	Fmod^tm1Aol/Fmod^tm1Aol Lum^tm1Chak/Lum^+	involves: 129S1/Sv * 129X1/SvJ * CD-1	MGI:3050098

Genotype
MGI:3047689

hm1

• 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 corneal 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 corneal 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 corneal 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)

corneal 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

Genotype
MGI:3047839

cx2

• Allelic Composition: Fmod^tm1Aol/Fmod^tm1Aol; Lum^tm1Chak/Lum^tm1Chak
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * CD-1

Fmod^tm1Aol/Fmod^tm1Aol Lum^tm1Chak/Lum^tm1Chak mice display decreased body size, abnormal gait and abnormal limb morphology

behavior/neurological

abnormal gait ( J:79115 )

• double homozygotes exhibit a severe gait impairment and walk on the dorsal part of the foot

cardiovascular system

abnormal blood vessel morphology ( J:79115 )

• double homozygotes show increased vasculature of the myocardium

abnormal myocardial fiber morphology ( J:79115 )

• double homozygotes display myofiber disorganization but no signs of fibrosis

decreased heart weight ( J:79115 )

• in double mutant mice, the weight of the whole heart, normalized for body weight, is decreased relative to wild-type

bruising ( J:79115 )

• double homozygotes bruise easily

growth/size/body

decreased body size ( J:79115 )

• double mutants are viable and fertile but significantly smaller than wild-type

decreased body weight ( J:79115 )

• double homozygotes show a 23% reduction in body weight relative to wild-type

immune system

osteoarthritis ( J:79115 )

• double mutants display age-dependent osteoarthritis

limbs/digits/tail

abnormal limb morphology ( J:79115 )

• double homozygotes have bowed legs

abnormal femur morphology ( J:79115 )

• the distal femur shows a hypertrophic response, providing extra trabecular tissue to support the misaligned patella

abnormal patella morphology ( J:79115 )

• double homozygotes display a 2-fold increase in knee joint deflection, indicating increased joint laxity

• 65% of double homozygotes show a medial misalignment of the patella and a secondary patellar groove

muscle

abnormal myocardial fiber morphology ( J:79115 )

• double homozygotes display myofiber disorganization but no signs of fibrosis

abnormal tendon morphology ( J:79115 )

• at 5 months, tendons from double mutants show abnormal collagen fibrils, many with cauliflower-like contours, indicating abnormal lateral growth

• as in the wild-type, the small diameter fibrils constitute ~25% of the total population in double mutant mice; however, the large diameter population increases to 32% (vs 28% in wild-type), with 7% (vs 5% in wild-type) in the >220-nm range

decreased tendon stiffness ( J:83544 )

• double mutants show a 61% reduction in tendon stiffness and a 49% reduction in tensile modulus relative to wild-type

• the magnitude of reduction in stiffness associated with fibromodulin deficiency depends on the number of functional lumican alleles

muscle weakness ( J:79115 )

• double homozygotes display extreme loss of tendon strength

skeleton

osteoarthritis ( J:79115 )

• double mutants display age-dependent osteoarthritis

abnormal femur morphology ( J:79115 )

• the distal femur shows a hypertrophic response, providing extra trabecular tissue to support the misaligned patella

abnormal patella morphology ( J:79115 )

• double homozygotes display a 2-fold increase in knee joint deflection, indicating increased joint laxity

• 65% of double homozygotes show a medial misalignment of the patella and a secondary patellar groove

abnormal tendon morphology ( J:79115 )

• at 5 months, tendons from double mutants show abnormal collagen fibrils, many with cauliflower-like contours, indicating abnormal lateral growth

• as in the wild-type, the small diameter fibrils constitute ~25% of the total population in double mutant mice; however, the large diameter population increases to 32% (vs 28% in wild-type), with 7% (vs 5% in wild-type) in the >220-nm range

decreased tendon stiffness ( J:83544 )

• double mutants show a 61% reduction in tendon stiffness and a 49% reduction in tensile modulus relative to wild-type

• the magnitude of reduction in stiffness associated with fibromodulin deficiency depends on the number of functional lumican alleles

abnormal articular cartilage morphology ( J:79115 )

• by 5 months, double homozygotes exhibit severe articular cartilage degeneration due to abnormal usage of the joint

vision/eye

corneal opacity ( J:83544 )

• corneas from double homozygotes appear cloudy and slightly granular relative to wild-type

abnormal eye size ( J:83544 )

• the double mutant eyes are more elliptical and show a 10% increase in ocular axial length relative to wild-type

• in double homozygotes, the lower the body weight, the greater the ocular axial length

retina detachment ( J:83544 )

• at 1-5 months, 80% of double mutant eyes exhibit several areas of retinal detachment with extensive subretinal debris

abnormal sclera morphology ( J:83544 )

• posterior scleras have a larger fraction of cauliflower-like collagen fibrils, as well as localized areas of small- to very large-diameter fibrils of aberrant contour

sclera thinning ( J:83544 )

• in double homozygotes, the posterior sclera is significantly thinner

• consistent with sclera thinning, the mean number of collagen fibril lamella across the sclera is reduced

• double mutant scleras show significantly higher lamellar disorganization, more fibril-poor areas and abnormal fibril packing relative to wild-type or to either single mutant

high myopia ( J:83544 )

• taken together, double homozygotes show some of the key features of high myopia, including sclera thinning, increased ocular length, and retinal detachment

integument

loose skin ( J:79115 )

• double homozygotes exhibit skin laxity and fragility

decreased skin tensile strength ( J:79115 )

• double homozygotes display a 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:79115

Genotype
MGI:3050098

cx3

• Allelic Composition: Fmod^tm1Aol/Fmod^tm1Aol; Lum^tm1Chak/Lum⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * CD-1

muscle

decreased tendon stiffness ( J:83544 )

• compound mutant mice show a 45% reduction in tendon stiffness and a 29% reduction in tensile modulus relative to wild-type

• the severity of stiffness reduction increases with the loss of each functional lumican allele in a lumican dose-dependent fashion

skeleton

decreased tendon stiffness ( J:83544 )

• compound mutant mice show a 45% reduction in tendon stiffness and a 29% reduction in tensile modulus relative to wild-type

• the severity of stiffness reduction increases with the loss of each functional lumican allele in a lumican dose-dependent fashion