Phenotypes associated with this allele

• Allele Symbol: Nipbl^{Gt(RRS564)Byg}
• Allele Name: gene trap RRS564, BayGenomics
• Allele ID: MGI:4332250
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Nipbl^Gt(RRS564)Byg/Nipbl^+	involves: 129P2/OlaHsd * C57BL/6J * CD-1	MGI:7491942
ht2	Nipbl^Gt(RRS564)Byg/Nipbl^+	involves: 129P2/OlaHsd * CD-1	MGI:4367868
cx3	Nipbl^Gt(RRS564)Byg/Nipbl^+ Nkx2-5^tm1(cre)Rjs/Nkx2-5^+	involves: 129P2/OlaHsd * 129S7/SvEvBrd * CD-1	MGI:7492254
cx4	Eif2ak2^tm1Cwe/Eif2ak2^tm1Cwe Nipbl^Gt(RRS564)Byg/Nipbl^+	involves: 129/Sv * 129P2/OlaHsd * C57BL/6J * CD-1	MGI:7491947

Genotype
MGI:7491942

ht1

• Allelic Composition: Nipbl^{Gt(RRS564)Byg}/Nipbl⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * CD-1

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

mortality/aging

postnatal lethality, incomplete penetrance ( J:297059 )

• only about 32% of of mice are viable after birth

embryo

decreased embryo weight ( J:297059 )

• 15% reduction in weight at E14.5

• a wild-type embryo with a heterozygous placenta also shows embryonic growth impairment

abnormal placenta junctional zone morphology ( J:297059 )

• increase in the junctional zone

abnormal spongiotrophoblast cell morphology ( J:297059 )

• spongiotrophoblasts have more diploid DNA content at E14.5

abnormal placenta labyrinth morphology ( J:297059 )

• mislocalized cells from the junctional zone are present in the labyrinth zone

increased placenta weight ( J:297059 )

• placentas are 8% heavier at E14.5

abnormal placenta physiology ( J:297059 )

• increased secretion of CCL2 from the placenta at E14.5

• reduced IkappaBalpha in the junctional zone and labyrinth zone at E14.5

• elevated gammaH2A.X signalling indicating decreased DNA repair and persistence of DNA damage in trophoblast giant cells and spongiotrophoblasts but not in glycogen cells in the placenta

• at E14.5 but not E9.5 elevated signals of senescence are seen in spongiotrophoblasts

cellular

abnormal chromosome number ( J:297059 )

• spongiotrophoblasts have more diploid DNA content at E14.5

abnormal DNA repair ( J:297059 )

• elevated gammaH2A.X signalling indicating decreased DNA repair and persistence of DNA damage in trophoblast giant cells and spongiotrophoblasts but not in glycogen cells in the placenta

skeleton

decreased bone ossification ( J:297059 )

• in the jawbone

homeostasis/metabolism

abnormal DNA repair ( J:297059 )

• elevated gammaH2A.X signalling indicating decreased DNA repair and persistence of DNA damage in trophoblast giant cells and spongiotrophoblasts but not in glycogen cells in the placenta

abnormal chemokine level ( J:297059 )

• increased secretion of CCL2 by the placenta at E14.5 and a 2-fold increase in CCL2 levels in the embryo compared to controls at E18.5

growth/size/body

decreased embryo weight ( J:297059 )

• 15% reduction in weight at E14.5

• a wild-type embryo with a heterozygous placenta also shows embryonic growth impairment

immune system

abnormal chemokine level ( J:297059 )

• increased secretion of CCL2 by the placenta at E14.5 and a 2-fold increase in CCL2 levels in the embryo compared to controls at E18.5

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Cornelia de Lange syndrome 1		DOID:0080505	OMIM:122470	J:297059

Genotype
MGI:4367868

ht2

• Allelic Composition: Nipbl^{Gt(RRS564)Byg}/Nipbl⁺
• Genetic Background: involves: 129P2/OlaHsd * CD-1

Bone and heart development abnormalities in Nipbl^{Gt(RRS564)Byg}/Nipbl⁺ mice

mortality/aging

premature death ( J:154117 )

• although present in normal Mendelian ratios at E17.5 and E18.5, 75% to 80% of mice die prior to 4 weeks of age

postnatal lethality ( J:154117 )

muscle

abnormal myocardium compact layer morphology ( J:154117 )

• many mice exhibit disorganized compact layer, especially near the apex, unlike in wild-type mice

abnormal ventricle myocardium morphology ( J:154117 )

• many mice exhibit abnormal ventricular and interventricular myocardium, including abnormal lacunar structures, compared with wild-type mice

growth/size/body

decreased birth body size ( J:154117 )

decreased body weight ( J:154117 )

• body weight is decreased 40% to 50% compared to wild-type mice

• by 9 weeks, mice weight 65% to 70% of wild-type

abnormal head morphology ( J:154117 )

midface hypoplasia ( J:154117 )

• mice exhibit a sunken mid-face unlike wild-type mice

upturned snout ( J:154117 )

shortened head ( J:154117 )

microcephaly ( J:154117 )

abnormal postnatal growth ( J:154117 )

postnatal growth retardation ( J:154117 )

• during the first weeks of life, mice fail to thrive and undergo several days of wasting followed by death unlike wild-type mice

decreased fetal size ( J:154117 )

• 18% to 19% smaller than wild-type at E17.5 to E18.5

decreased fetal weight ( J:154117 )

• at E17.5 to E18.5, mice weight is 18% to 19% less than in wild-type mice

cardiovascular system

cardiovascular system phenotype ( J:154117 )

N • no abnormalities detected in the atrioventricular valves or septum, outflow tract, or pulmonary vasculature

abnormal heart morphology ( J:154117 )

• many mice exhibit abnormal heart morphology compared with wild-type mice

• however, mice that survive the perinatal period exhibit normal heart morphology

abnormal myocardium compact layer morphology ( J:154117 )

• many mice exhibit disorganized compact layer, especially near the apex, unlike in wild-type mice

abnormal ventricle myocardium morphology ( J:154117 )

• many mice exhibit abnormal ventricular and interventricular myocardium, including abnormal lacunar structures, compared with wild-type mice

heart atrium hypoplasia ( J:154117 )

• in some mice

abnormal heart septum morphology ( J:154117 )

• in 50% of mice as early as E15.5

atrial septal defect ( J:154117 )

• in 58% of mice between E15.5 and E17.5

abnormal interventricular septum morphology ( J:236978 )

• at E13.5 77% of hearts show incomplete fusion or lack of contact of the developing septum with the cardiac cushion increased compare to 14% of wild-type hearts

• however, at E17.5 ventricular septal defects are not typically seen

ventricular septal defect ( J:154117 )

decreased heart right ventricle size ( J:236978 )

• at E10.5

skeleton

abnormal craniofacial bone morphology ( J:154117 )

• skull bone thickness is reduced compared to in wild-type mice

abnormal neurocranium morphology ( J:154117 )

• mice exhibit a 25% reduction in endocranial volume compared with wild-type mice

abnormal sphenoid bone morphology ( J:154117 )

• the sphenoid bone is reduced compared to in wild-type mice

small ethmoid bone ( J:154117 )

• the ethmoid bone is reduced compared to in wild-type mice

decreased length of long bones ( J:154117 )

• at E17.5

delayed endochondral bone ossification ( J:154117 )

delayed intramembranous bone ossification ( J:154117 )

vision/eye

eye inflammation ( J:154117 )

• some mice exhibit inflammatory and fibrotic change consistent with repeated abrasion or injury unlike wild-type mice

abnormal eye morphology ( J:154117 )

• 22% of mice exhibit opthalmological defects unlike wild-type mice

• as early as 3 weeks of age, 14% of mice exhibit ocular opacification unlike wild-type mice

abnormal eyelid morphology ( J:154117 )

• some mice exhibit periorbital inflammation that progresses to permanent closure of eyelids unlike in wild-type mice

behavior/neurological

abnormal behavioral response to anesthetic ( J:154117 )

• 30% of mice treated with a normal dose of the anesthetic avertin adopt an opisthotonic position unlike similarly treated wild-type mice

limb grasping ( J:154117 )

• in 15% of mice compared with 2% of wild-type mice

circling ( J:154117 )

• in 20% of mice

nervous system

decreased brain size ( J:154117 )

decreased corpus callosum size ( J:154117 )

absent corpus callosum ( J:154117 )

• in some mice

abnormal cerebellum morphology ( J:154117 )

• lobe IX exhibits a specific reduction compared to in wild-type mice

hearing/vestibular/ear

abnormal auditory brainstem response ( J:154117 )

• in a few mice

abnormal auditory brainstem response waveform shape ( J:154117 )

• nearly all mice exhibit abnormal relative intensities of the components of the brainstem auditory evoked potential compared with wild-type mice

• peak III is reduced compared to in wild-type mice

cellular

abnormal cell differentiation ( J:154117 )

• mice embryonic fibroblasts exhibit less spontaneous differentiation into adipocytes compared with wild-type cells

• however, induced adipogenesis of mouse embryonic fibroblasts is normal

immune system

abnormal inflammatory response ( J:154117 )

• some mice exhibit periorbital inflammation that progresses to permanent closure of eyelids unlike in wild-type mice

eye inflammation ( J:154117 )

• some mice exhibit inflammatory and fibrotic change consistent with repeated abrasion or injury unlike wild-type mice

limbs/digits/tail

brachydactyly ( J:154117 )

• at E17.5

craniofacial

abnormal craniofacial bone morphology ( J:154117 )

• skull bone thickness is reduced compared to in wild-type mice

abnormal neurocranium morphology ( J:154117 )

• mice exhibit a 25% reduction in endocranial volume compared with wild-type mice

abnormal sphenoid bone morphology ( J:154117 )

• the sphenoid bone is reduced compared to in wild-type mice

small ethmoid bone ( J:154117 )

• the ethmoid bone is reduced compared to in wild-type mice

midface hypoplasia ( J:154117 )

• mice exhibit a sunken mid-face unlike wild-type mice

upturned snout ( J:154117 )

shortened head ( J:154117 )

adipose tissue

decreased brown adipose tissue amount ( J:154117 )

decreased white adipose tissue amount ( J:154117 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Cornelia de Lange syndrome 1		DOID:0080505	OMIM:122470	J:154117

Genotype
MGI:7492254

cx3

• Allelic Composition: Nipbl^{Gt(RRS564)Byg}/Nipbl⁺; Nkx2-5^tm1(cre)Rjs/Nkx2-5⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S7/SvEvBrd * CD-1

cardiovascular system

abnormal heart morphology ( J:236978 )

• increased incidence of heart defects compared to mice heterozygous for the Nipbl allele alone (83% compared to 30%)

• spectrum of defects is more varied in type and more severe than in mice heterozygous for the Nipbl allele alone

persistent truncus arteriosus ( J:236978 )

• in 2 heartts

atrial septal defect ( J:236978 )

• sometimes seen in combination with ventricular septal defects

ventricular septal defect ( J:236978 )

• sometimes seen in combination with atrial septal defects

Genotype
MGI:7491947

cx4

• Allelic Composition: Eif2ak2^tm1Cwe/Eif2ak2^tm1Cwe; Nipbl^{Gt(RRS564)Byg}/Nipbl⁺
• Genetic Background: involves: 129/Sv * 129P2/OlaHsd * C57BL/6J * CD-1

mortality/aging

postnatal lethality, incomplete penetrance ( J:297059 )

• viability is increased up to 63% for mutant mice homozygous for the mutation in Eif2ak2 compared to mutant mice wild-type for Eif2ak2 (~32% viability)

embryo

abnormal placenta junctional zone morphology ( J:297059 )

• increase in the junctional zone

abnormal spongiotrophoblast cell morphology ( J:297059 )

• spongiotrophoblasts have more diploid DNA content at E14.5

abnormal trophoblast glycogen cell morphology ( J:297059 )

• increased diploid DNA content at E14.5

skeleton

abnormal bone ossification ( J:297059 )

• ossification in the jawbone is improved compared to mutant mice wild-type for Eif2ak2

cellular

abnormal chromosome number ( J:297059 )

• spongiotrophoblasts and glycogen cells have more diploid DNA content at E14.5

abnormal DNA repair ( J:297059 )

• elevated gammaH2A.X signalling indicating decreased DNA repair and persistence of DNA damage in spongiotrophoblasts

homeostasis/metabolism

abnormal DNA repair ( J:297059 )

• elevated gammaH2A.X signalling indicating decreased DNA repair and persistence of DNA damage in spongiotrophoblasts