Phenotypes Associated with This Genotype

Genotype
MGI:3845065

• Allelic Composition: Hras^tm1Jaf/Hras⁺; Tg(CAG-cre)13Miya/0
• Genetic Background: involves: 129S6/SvEvTac * Black Swiss * C57BL/6

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

mortality/aging

premature death ( J:148393 )

• mice that survive until weaning continue to have a high mortality rate

postnatal lethality, incomplete penetrance ( J:148393 )

• greater than 80% of pups die in the first two weeks of life

craniofacial

abnormal tooth development ( J:204891 )

• mice show residual enamel matrix, indicating that ameloblasts do not completely remove the enamel matrix to form properly mineralized enamel

• increase in proliferation of progenitor cells in the cervical loop and transit-amplifying region of the tooth and the length of the transit-amplifying region is shorter

abnormal cervical loop morphology ( J:204891 )

• increase in proliferation of progenitor cells in the cervical loop

abnormal stellate reticulum morphology ( J:204891 )

• the stellate reticulum is disorganized

abnormal stratum intermedium morphology ( J:204891 )

• ameloblasts and the underlying stratum intermedium are disorganized and the well-defined border between ameloblasts and stratum intermedium is lost

abnormal enamel morphology ( J:204891 )

• mice show residual enamel matrix, indicating that ameloblasts do not completely remove the enamel matrix to form properly mineralized enamel

abnormal ameloblast morphology ( J:148393 , J:204891 )

• growth of ameloblasts is disorganized with detachment of the ameloblasts from the adjacent dentin, loss of polarity, and stratification occurring (J:148393)

• ameloblasts are disorganized, crowded and there is an increase in the number of ameloblasts at both the secretory and maturation stages (J:204891)

• ameloblasts have abnormal cell polarity at the secretory and maturation stages, with misorientation of nuclei and Golgi (J:204891)

abnormal ameloblast differentiation ( J:204891 )

• teeth show an increase in the distance between the cervical loop region and the appearance of the enamel protein amelogenin compared with controls, suggesting that ameloblasts show a delay in differentiation

abnormal enamel mineralization ( J:148393 , J:204891 )

• mice have irregular deposition of enamel (J:148393)

• incisor enamel is less densely mineralized at all stages examined and total volume of enamel is decreased, with enamel covering a decreased percent of the surface area of the tooth (J:204891)

abnormal enamel rod pattern ( J:204891 )

• the interdigitated and highly organized pattern is lost in the enamel of incisors and the enamel rods intersect at irregular angles and do not completely span the dentin-enamel junction to the enamel surface

absent enamel ( J:204891 )

• molars show little to no enamel

• treatment of mice with a MEK inhibitor for 28 days rescues the enamel defect

malocclusion ( J:148393 )

• malocclusion occurs in these mice

jaw cyst ( J:204891 )

• large cysts in the bone in the region of the third molar at P21

• cysts are lined by epithelium infiltrated by ghost cells, or aneucleic cells with basophilic granules

• cysts are near, but not associated with, the third molar, suggesting calcifying odontogenic cysts

• cysts are not observed at P70, indicating they resolve in adulthood

domed cranium ( J:148393 )

• the ratio of the cephalo-caudal to ventro-dorsal cranial axes is significantly smaller than controls

deviated nasal septum ( J:148393 )

• nasal septal deviation is prominent in these mice

growth/size/body

abnormal tooth development ( J:204891 )

• mice show residual enamel matrix, indicating that ameloblasts do not completely remove the enamel matrix to form properly mineralized enamel

• increase in proliferation of progenitor cells in the cervical loop and transit-amplifying region of the tooth and the length of the transit-amplifying region is shorter

abnormal cervical loop morphology ( J:204891 )

• increase in proliferation of progenitor cells in the cervical loop

abnormal stellate reticulum morphology ( J:204891 )

• the stellate reticulum is disorganized

abnormal stratum intermedium morphology ( J:204891 )

• ameloblasts and the underlying stratum intermedium are disorganized and the well-defined border between ameloblasts and stratum intermedium is lost

abnormal enamel morphology ( J:204891 )

• mice show residual enamel matrix, indicating that ameloblasts do not completely remove the enamel matrix to form properly mineralized enamel

abnormal ameloblast morphology ( J:148393 , J:204891 )

• growth of ameloblasts is disorganized with detachment of the ameloblasts from the adjacent dentin, loss of polarity, and stratification occurring (J:148393)

• ameloblasts are disorganized, crowded and there is an increase in the number of ameloblasts at both the secretory and maturation stages (J:204891)

• ameloblasts have abnormal cell polarity at the secretory and maturation stages, with misorientation of nuclei and Golgi (J:204891)

abnormal ameloblast differentiation ( J:204891 )

• teeth show an increase in the distance between the cervical loop region and the appearance of the enamel protein amelogenin compared with controls, suggesting that ameloblasts show a delay in differentiation

abnormal enamel mineralization ( J:148393 , J:204891 )

• mice have irregular deposition of enamel (J:148393)

• incisor enamel is less densely mineralized at all stages examined and total volume of enamel is decreased, with enamel covering a decreased percent of the surface area of the tooth (J:204891)

abnormal enamel rod pattern ( J:204891 )

• the interdigitated and highly organized pattern is lost in the enamel of incisors and the enamel rods intersect at irregular angles and do not completely span the dentin-enamel junction to the enamel surface

absent enamel ( J:204891 )

• molars show little to no enamel

• treatment of mice with a MEK inhibitor for 28 days rescues the enamel defect

malocclusion ( J:148393 )

• malocclusion occurs in these mice

jaw cyst ( J:204891 )

• large cysts in the bone in the region of the third molar at P21

• cysts are lined by epithelium infiltrated by ghost cells, or aneucleic cells with basophilic granules

• cysts are near, but not associated with, the third molar, suggesting calcifying odontogenic cysts

• cysts are not observed at P70, indicating they resolve in adulthood

deviated nasal septum ( J:148393 )

• nasal septal deviation is prominent in these mice

postnatal growth retardation ( J:148393 )

• mice that survive until weaning are runted but catch up in weight to controls by 20 weeks of age

behavior/neurological

abnormal suckling behavior ( J:148393 )

• the high mortality rate of neonates and the abnormal cranial/facial structures suggests pups have trouble suckling

neoplasm

increased stomach tumor incidence ( J:148393 )

• almost all mice develop papillomas in the forestomach by 13 months of age

increased hemangiosarcoma incidence ( J:148393 )

• angiosarcomas develop in about 40% of older mice

increased papilloma incidence ( J:148393 )

• papillomas are occasionally found in the anal epithelium

increased skin papilloma incidence ( J:148393 )

• 88% of mice develop skin papillomas by 58 weeks of age

• they are frequently found in the skull, face, and external auditory canal

cardiovascular system

cardiac fibrosis ( J:148393 )

• older mice (40-58 weeks) develop myocardial fibrosis

respiratory system

deviated nasal septum ( J:148393 )

• nasal septal deviation is prominent in these mice

skeleton

abnormal tooth development ( J:204891 )

• mice show residual enamel matrix, indicating that ameloblasts do not completely remove the enamel matrix to form properly mineralized enamel

• increase in proliferation of progenitor cells in the cervical loop and transit-amplifying region of the tooth and the length of the transit-amplifying region is shorter

abnormal cervical loop morphology ( J:204891 )

• increase in proliferation of progenitor cells in the cervical loop

abnormal stellate reticulum morphology ( J:204891 )

• the stellate reticulum is disorganized

abnormal stratum intermedium morphology ( J:204891 )

• ameloblasts and the underlying stratum intermedium are disorganized and the well-defined border between ameloblasts and stratum intermedium is lost

abnormal enamel morphology ( J:204891 )

• mice show residual enamel matrix, indicating that ameloblasts do not completely remove the enamel matrix to form properly mineralized enamel

abnormal ameloblast morphology ( J:148393 , J:204891 )

• growth of ameloblasts is disorganized with detachment of the ameloblasts from the adjacent dentin, loss of polarity, and stratification occurring (J:148393)

• ameloblasts are disorganized, crowded and there is an increase in the number of ameloblasts at both the secretory and maturation stages (J:204891)

• ameloblasts have abnormal cell polarity at the secretory and maturation stages, with misorientation of nuclei and Golgi (J:204891)

abnormal ameloblast differentiation ( J:204891 )

• teeth show an increase in the distance between the cervical loop region and the appearance of the enamel protein amelogenin compared with controls, suggesting that ameloblasts show a delay in differentiation

abnormal enamel mineralization ( J:148393 , J:204891 )

• mice have irregular deposition of enamel (J:148393)

• incisor enamel is less densely mineralized at all stages examined and total volume of enamel is decreased, with enamel covering a decreased percent of the surface area of the tooth (J:204891)

abnormal enamel rod pattern ( J:204891 )

• the interdigitated and highly organized pattern is lost in the enamel of incisors and the enamel rods intersect at irregular angles and do not completely span the dentin-enamel junction to the enamel surface

absent enamel ( J:204891 )

• molars show little to no enamel

• treatment of mice with a MEK inhibitor for 28 days rescues the enamel defect

malocclusion ( J:148393 )

• malocclusion occurs in these mice

jaw cyst ( J:204891 )

• large cysts in the bone in the region of the third molar at P21

• cysts are lined by epithelium infiltrated by ghost cells, or aneucleic cells with basophilic granules

• cysts are near, but not associated with, the third molar, suggesting calcifying odontogenic cysts

• cysts are not observed at P70, indicating they resolve in adulthood

domed cranium ( J:148393 )

• the ratio of the cephalo-caudal to ventro-dorsal cranial axes is significantly smaller than controls

integument

increased skin papilloma incidence ( J:148393 )

• 88% of mice develop skin papillomas by 58 weeks of age

• they are frequently found in the skull, face, and external auditory canal

digestive/alimentary system

increased stomach tumor incidence ( J:148393 )

• almost all mice develop papillomas in the forestomach by 13 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Costello syndrome		DOID:0050469	OMIM:218040	J:204891