Phenotypes associated with this allele

• Allele Symbol: Adamtsl2^{tm1a(KOMP)Wtsi}
• Allele Name: targeted mutation 1a, Wellcome Trust Sanger Institute
• Allele ID: MGI:4362645
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Adamtsl2^tm1a(KOMP)Wtsi/Adamtsl2^tm1a(KOMP)Wtsi	C57BL/6N-Adamtsl2^tm1a(KOMP)Wtsi/MbpMmucd	MGI:8243405
ht2	Adamtsl2^tm1a(KOMP)Wtsi/Adamtsl2^tm2Mtek	involves: C57BL/6N	MGI:8243419
ht3	Adamtsl2^tm1a(KOMP)Wtsi/Adamtsl2^tm1Mtek	involves: C57BL/6N	MGI:8243426

Genotype
MGI:8243405

hm1

• Allelic Composition: Adamtsl2^{tm1a(KOMP)Wtsi}/Adamtsl2^{tm1a(KOMP)Wtsi}
• Genetic Background: C57BL/6N-Adamtsl2^{tm1a(KOMP)Wtsi}/MbpMmucd
• Cell Lines: EPD0073_3_E06

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

mortality/aging

postnatal lethality, complete penetrance ( J:345629 )

• the couple of mice that survive after birth die by P30

neonatal lethality, incomplete penetrance ( J:345629 )

• mice die shortly after birth except for a couple of mice that survive but die by P30

growth/size/body

postnatal growth retardation ( J:345629 )

• no weight difference is seen at birth, but one male that survived to 30 days was smaller and underweight at 3 weeks of age

Genotype
MGI:8243419

ht2

• Allelic Composition: Adamtsl2^{tm1a(KOMP)Wtsi}/Adamtsl2^tm2Mtek
• Genetic Background: involves: C57BL/6N

mortality/aging

premature death ( J:345629 )

• mice exhibit a significant reduction of survival during the first 6 months of life, with approximately 70% of mice surviving after birth and about 40% surviving after P120

neonatal lethality, incomplete penetrance ( J:345629 )

• approximately 70% of mice survive after birth, indicating around 30% lethality around birth

growth/size/body

cardiac hypertrophy ( J:345629 )

• hearts show hypertrophic cardiomyopathy along with myocyte hypertrophy of varying severity

short nasal bone ( J:345629 )

short snout ( J:345629 )

slow postnatal weight gain ( J:345629 )

• mice show reduced weight gain starting from 3-4 weeks of age

cardiovascular system

supravalvar aortic stenosis ( J:345629 )

• narrowing of the aortic root is seen in all mice

abnormal myocardium layer morphology ( J:345629 )

• mice show elevated proteoglycan staining in the myocardium and chondroid metaplasia, along with patchy mild interstitital fibrosis within the myocardiaum

abnormal atrium myocardium morphology ( J:345629 )

• some mice with cardiac fibrosis have histologic evidence of small areas with chondroid metaplasia localized mainly in the atrium and the aortic valve

cardiac hypertrophy ( J:345629 )

• hearts show hypertrophic cardiomyopathy along with myocyte hypertrophy of varying severity

abnormal aortic valve morphology ( J:345629 )

• some mice with cardiac fibrosis have histologic evidence of small areas with obvious chondroid metaplasia localized mainly in the aortic valve and the atrium

cardiac interstitial fibrosis ( J:345629 )

• patchy mild interstitial cardiac fibrosis is seen in the most severely affected mice

decreased cardiac output ( J:345629 )

decreased cardiac stroke volume ( J:345629 )

decreased heart ventricle muscle contractility ( J:345629 )

• mice show reduced ejection fraction, stroke volume, cardiac output, and fractional shortening, increased left ventricular end-systolic internal diameter (LVID) and increased end-systolic volume (ESV) indicating systolic dysfunction indicative of inadequate ejection of blood from the heart chambers following each systolic contraction

abnormal heart echocardiography feature ( J:345629 )

• echocardiograms show reduced ejection fraction, stroke volume, cardiac output, and fractional shortening, increased left ventricular end-systolic internal diameter (LVID) and increased end-systolic volume (ESV) indicating systolic dysfunction indicative of inadequate ejection of blood from the heart chambers following each systolic contraction

• systolic dysfunction is progressive as LVID and ESV are increased at 20 weeks compared to 12 weeks

• the ratio of peak mitral inflow velocity during early diastole and mitral annular velocity is altered, indicating increased ventricular filling pressure

• increase in the left-ventricular end-systolic anterior wall thickness at 12 weeks of age

• pulmonary ejection time is reduced at 20 weeks, indicating increased afterload in the right ventricle, however, pulmonary acceleration time (PAT), and PAT/pulmonary ejection time are not altered and mean pulmonary artery pressure is not changed

• however, parameters of diastolic dysfunction, such as isovolumic relaxation time and mitral ratio of the early to late ventricular filling velocities, are not altered

abnormal heart valve physiology ( J:345629 )

• the pulmonary valve peak pressure is increased

• mice show a large variability of aortic valve peak pressure and aortic ejection time

cardiomyopathy ( J:345629 )

• hearts show hypertrophic cardiomyopathy along with myocyte hypertrophy of varying severity

• mice exhibit cardiac insufficiency and narrowing of the aortic and possibly pulmonary valve openings

• MRI shows that hearts are unable to pump all the blood and end-systolic images show that end-systolic ventricles are still full of blood

cellular

cardiac interstitial fibrosis ( J:345629 )

• patchy mild interstitial cardiac fibrosis is seen in the most severely affected mice

craniofacial

abnormal cranium morphology ( J:345629 )

• cranium is more rounded

short nasal bone ( J:345629 )

short snout ( J:345629 )

immune system

lung inflammation ( J:345629 )

• evidence of microscopic post-obstructive pneumonia is seen, characterized by accumulation of foamy macrophages within alveolar airspaces, in the most affected mice

limbs/digits/tail

abnormal phalanx morphology ( J:345629 )

• the third and fourth proximal phalanges show a width reduction

brachyphalangia ( J:345629 )

• proximal phalanges of second, third, and fourth digits from front paws are shorter

short femur ( J:345629 )

• femur length is shortened, but no difference is seen in width or cortical thickness

muscle

abnormal myocardium layer morphology ( J:345629 )

• mice show elevated proteoglycan staining in the myocardium and chondroid metaplasia, along with patchy mild interstitital fibrosis within the myocardiaum

abnormal atrium myocardium morphology ( J:345629 )

• some mice with cardiac fibrosis have histologic evidence of small areas with chondroid metaplasia localized mainly in the atrium and the aortic valve

decreased heart ventricle muscle contractility ( J:345629 )

• mice show reduced ejection fraction, stroke volume, cardiac output, and fractional shortening, increased left ventricular end-systolic internal diameter (LVID) and increased end-systolic volume (ESV) indicating systolic dysfunction indicative of inadequate ejection of blood from the heart chambers following each systolic contraction

cardiomyopathy ( J:345629 )

• hearts show hypertrophic cardiomyopathy along with myocyte hypertrophy of varying severity

• mice exhibit cardiac insufficiency and narrowing of the aortic and possibly pulmonary valve openings

• MRI shows that hearts are unable to pump all the blood and end-systolic images show that end-systolic ventricles are still full of blood

respiratory system

short nasal bone ( J:345629 )

lung inflammation ( J:345629 )

• evidence of microscopic post-obstructive pneumonia is seen, characterized by accumulation of foamy macrophages within alveolar airspaces, in the most affected mice

abnormal lung morphology ( J:345629 )

• MRI shows bilateral ground glass opacification with multifocal areas of poorly defined consolidation in the lungs of the most severe cases

• however, no significant pulmonary fibrosis is seen

abnormal respiratory function ( J:345629 )

• whole-body plethysmography at 12 weeks and 20 weeks of age indicates respiratory dysfunction in the expiration phase in some mice

• severity of respiratory insufficiency varies

• males exhibit a more severe respiratory dysfunction than females

• no significant progression of respiratory dysfunction is seen between 12 and 20 weeks

• mice show a more severe respiratory dysfunction than homozygous Adamts12^tm2Mtek mice

abnormal forced expiratory flow rates ( J:345629 )

• indicators of the expiration phase, including pause (Penh), pause index, and the peak expiratory flow/peak inspiratory flow ratio, are affected

• however, the inspiration phase and other parameters of respiration, including respiratory rate and tidal volume, are not altered

skeleton

abnormal cranium morphology ( J:345629 )

• cranium is more rounded

short nasal bone ( J:345629 )

abnormal phalanx morphology ( J:345629 )

• the third and fourth proximal phalanges show a width reduction

brachyphalangia ( J:345629 )

• proximal phalanges of second, third, and fourth digits from front paws are shorter

short femur ( J:345629 )

• femur length is shortened, but no difference is seen in width or cortical thickness

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
geleophysic dysplasia 1		DOID:0111725	OMIM:231050	J:345629

Genotype
MGI:8243426

ht3

• Allelic Composition: Adamtsl2^{tm1a(KOMP)Wtsi}/Adamtsl2^tm1Mtek
• Genetic Background: involves: C57BL/6N

cardiovascular system

cardiovascular system phenotype ( J:345629 )

N • mice do not show any significant cardiac pathology

craniofacial

abnormal cranium morphology ( J:345629 )

• cranium is more rounded

growth/size/body

decreased body weight ( J:345629 )

• mice show reduced weight gain after 2 to 3 months of age

limbs/digits/tail

brachyphalangia ( J:345629 )

• proximal phalanges of second, third, and fourth digits from front paws are shorter

short femur ( J:345629 )

• femur length is shortened, but to a smaller extent than in mice carrying the Adamtsl2^tm2Mtek allele, and no difference is seen in width or cortical thickness

mortality/aging

mortality/aging ( J:345629 )

N • mice exhibit normal survival

skeleton

abnormal cranium morphology ( J:345629 )

• cranium is more rounded

brachyphalangia ( J:345629 )

• proximal phalanges of second, third, and fourth digits from front paws are shorter

short femur ( J:345629 )

• femur length is shortened, but to a smaller extent than in mice carrying the Adamtsl2^tm2Mtek allele, and no difference is seen in width or cortical thickness

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
geleophysic dysplasia 1		DOID:0111725	OMIM:231050	J:345629