Phenotypes Associated with This Genotype

Genotype
MGI:4459466

• Allelic Composition: Lmna^Dhe/Lmna⁺
• Genetic Background: B6(D2)-Lmna^Dhe/TyGrsrJ

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

Lmna^Dhe/Lmna⁺ mice (right) have a sparse and gray coat, small size and small pinnae

mortality/aging

premature aging ( J:160175 )

• coat turns gray around 12 weeks of age

• however, lifespan is similar to controls

hematopoietic system

abnormal peritoneal macrophage morphology ( J:188496 )

• nuclear lamina meshwork of peritoneal macrophages appears rugous, disintegrative, or even collapsed and nuclear volumes are large

• however, mice exhibit normal macrophage migration elicited by thioglycollate

immune system

increased susceptibility to otitis media ( J:188496 )

• 100% penetrance of otitis media as early as P12

• cells of acute inflammatory response begin to perfuse the middle ear cavity, to infiltrate the mesenchymal cells and to block the Eustachian tube at P12

• at 8 weeks of age, cells of chronic inflammatory response pervade the entire middle ear cavity

• acute inflammatory cells and plasma fluids infiltrate the middle ear cavity extensively at P30

• from 2-8 months, various chronic suppurative middle ear inflammation occurs, with or without cholesteatoma

• macrophage activation is observed

abnormal peritoneal macrophage morphology ( J:188496 )

• nuclear lamina meshwork of peritoneal macrophages appears rugous, disintegrative, or even collapsed and nuclear volumes are large

• however, mice exhibit normal macrophage migration elicited by thioglycollate

craniofacial

abnormal cranial suture morphology ( J:160175 )

• patent sutures, in all cranial vault and facial sutures including the premaxillary/maxillary sutures

abnormal coronal suture morphology ( J:160175 )

• at six weeks the parietal and interparietal bones do not overlap and the suture tissue is hypoplastic, forming a much looser, thinner connection of the plates

abnormal lambdoid suture morphology ( J:160175 )

• suture tissue is hypoplastic, forming a much looser, thinner connection of the

abnormal sagittal suture morphology ( J:160175 )

• at 1 week of age, there is a gap between the the edges of the parietal bones and these bones are connected by a much thinner band of connective tissue

abnormal frontonasal suture morphology ( J:160175 )

• suture tissue is hypoplastic, forming a much looser, thinner connection of the plates

abnormal cranium size ( J:160175 )

• shorter, wider skull

decreased cranium height ( J:160175 )

decreased cranium width ( J:160175 )

small cranium ( J:160175 )

• in keeping with the reduction in body size

abnormal neurocranium morphology ( J:160175 )

• bone growth deficiency

shallow orbits ( J:160175 )

short upper incisors ( J:160175 )

• maxillary incisor and the diastema (the maxillary arch) are both abnormally short in the mutant

malocclusion ( J:160175 )

mandible hypoplasia ( J:160175 )

• underdeveloped lower jaw, inferior brachygnathism

short maxilla ( J:160175 )

• superior brachygnathism

short snout ( J:160175 )

• decreased nose length

short ears ( J:160175 )

• short pinnae

hearing/vestibular/ear

abnormal ear morphology ( J:188496 )

• ear hyperemia

short ears ( J:160175 )

• short pinnae

abnormal auditory bulla morphology ( J:188496 )

• bullae are smaller

abnormal middle ear morphology ( J:188496 )

• middle ear is undeveloped at P6

• middle ear cholesteatoma is seen in some ears

• typical cholesterol crystals are encysted by the hyperproliferative mucous epithelium and necrotic keratinizing squamous epithelial debris

• local suppurative abscess form in some middle ear cavities

abnormal middle ear development ( J:188496 )

• middle ear is undeveloped at P6

• the tympanic membrane is undeveloped at P12

abnormal auditory tube morphology ( J:188496 )

• abnormal positioning of the Eustachian tube with a greater mean intersection angle

• the mean length of the bony part of the Eustachian tube is smaller and width is greater than in wild-type resulting in a dilated anamorphic Eustachian tube

• at P12, with middle ear cavitation still progressing, dysplasia with dilation of the Eustachian tube is seen

• at 8 weeks of age, the Eustachian tube is distorted with dilation and exhibits poorly aligned and shorted or obsolescent cilia

abnormal middle ear epithelium morphology ( J:188496 )

• by 10 weeks of age, the cilia of the middle ear pseudostratified ciliated columnar epithelium exhibits severe pathology indicative of otitis media progression

increased middle ear goblet cell number ( J:188496 )

• proliferative goblet cells in the middle ear

abnormal tympanic membrane morphology ( J:188496 )

• tympanic membrane adherence

• the tympanic membrane is undeveloped at P12

• tympanic membrane shows a shortened subuliform light cone

tympanic membrane retraction ( J:188496 )

• at 8 weeks of age, the tympanic membrane is thickened and retracts into the middle ear cavity

abnormal ear physiology ( J:188496 )

• tympanometry shows that tympanometric values of volume are lower at 3 weeks of age but not other ages, values of compliance are lower at all time points from 3 weeks to 8 months of age, pressure of the middle ear is more negative, mean gradient values are higher at 1 month of age and 5 month old mice show an abnormal C type curve instead of the normal A type curve in scanning tympanograms

increased or absent threshold for auditory brainstem response ( J:188496 )

• ABR threshold from P16 to 4 months of age are elevated

abnormal distortion product otoacoustic emission ( J:188496 )

• at 3 months of age, mice have distortion product otoacoustin emission (DPOAE) 10-43.5 dB lower than those of wild-type mice

impaired hearing ( J:188496 )

• hearing impairment begins at lower stimulus frequencies (click and 8 kHz) and higher stimulus frequencies become affected with age

increased susceptibility to otitis media ( J:188496 )

• 100% penetrance of otitis media as early as P12

• cells of acute inflammatory response begin to perfuse the middle ear cavity, to infiltrate the mesenchymal cells and to block the Eustachian tube at P12

• at 8 weeks of age, cells of chronic inflammatory response pervade the entire middle ear cavity

• acute inflammatory cells and plasma fluids infiltrate the middle ear cavity extensively at P30

• from 2-8 months, various chronic suppurative middle ear inflammation occurs, with or without cholesteatoma

• macrophage activation is observed

respiratory system

abnormal nasopharynx morphology ( J:188496 )

• roof of the nasopharynx is abnormal as there is barely a gap between the tissue of the nasopharynx and the palate and the roof the nasopharynx is nearly fused to the palate bone

skeleton

abnormal cranial suture morphology ( J:160175 )

• patent sutures, in all cranial vault and facial sutures including the premaxillary/maxillary sutures

abnormal coronal suture morphology ( J:160175 )

• at six weeks the parietal and interparietal bones do not overlap and the suture tissue is hypoplastic, forming a much looser, thinner connection of the plates

abnormal lambdoid suture morphology ( J:160175 )

• suture tissue is hypoplastic, forming a much looser, thinner connection of the

abnormal sagittal suture morphology ( J:160175 )

• at 1 week of age, there is a gap between the the edges of the parietal bones and these bones are connected by a much thinner band of connective tissue

abnormal frontonasal suture morphology ( J:160175 )

• suture tissue is hypoplastic, forming a much looser, thinner connection of the plates

abnormal cranium size ( J:160175 )

• shorter, wider skull

decreased cranium height ( J:160175 )

decreased cranium width ( J:160175 )

small cranium ( J:160175 )

• in keeping with the reduction in body size

abnormal neurocranium morphology ( J:160175 )

• bone growth deficiency

shallow orbits ( J:160175 )

short upper incisors ( J:160175 )

• maxillary incisor and the diastema (the maxillary arch) are both abnormally short in the mutant

malocclusion ( J:160175 )

mandible hypoplasia ( J:160175 )

• underdeveloped lower jaw, inferior brachygnathism

short maxilla ( J:160175 )

• superior brachygnathism

decreased bone mineral content ( J:160175 )

• of skull

decreased bone mineral density ( J:160175 )

• low bone mineral density of skull and whole body

abnormal bone mineralization ( J:160175 )

• skull mineralization defects

adipose tissue

decreased total body fat amount ( J:160175 )

• in males

pigmentation

abnormal coat/hair pigmentation ( J:160175 )

• turns gray around 12 weeks of age

cellular

abnormal cell nucleus morphology ( J:171665 )

• nuclei appear larger and nuclear volume is greater than in wild-type mice

aneuploidy ( J:171665 )

• fibroblasts exhibit extensive aneuploidy, with a higher fraction of cells greater than 4C and chromosome numbers ranging from 38 to 104 chromosomes per nucleus

abnormal nuclear lamina morphology ( J:160175 , J:171665 , J:188496 )

• grossly abnormal nuclear lamina of cultured primary calvarial osteoblasts with various numbers of nuclear lamina blebs, discreet balloon-like outpocketings of the nuclear envelope (J:160175)

• skin fibroblasts exhibit aberrant nuclear lamina morphology, with nuclear membranes showing large blebs and lobulations (J:171665)

• patches of irregularity in the normal criss-cross pattern of LMNA and LMNB meshworks are seen (J:171665)

• nuclear lamina meshwork of peritoneal macrophages appears rugous, disintegrative, or even collapsed (J:188496)

increased middle ear goblet cell number ( J:188496 )

• proliferative goblet cells in the middle ear

abnormal cell cycle ( J:171665 )

• mutant cell cultures have an increased proportion of cells in anaphase compared to normal cells

abnormal mitosis ( J:171665 )

• mitotic defects such as aneuploidy, lagging chromosomes, and anaphase bridges associated with low levels of activated RB1 and CAPD3

• LMNA expression and assembly at the nuclear lamina is perturbed during interphase and mitosis

• fibroblasts exhibit mitotic chromosome cohesion defects

abnormal mitotic spindle assembly checkpoint ( J:171665 )

• defects in mitotic spindle checkpoint

decreased fibroblast proliferation ( J:171665 )

• fibroblasts grow significantly slower that wild-type fibroblasts

abnormal DNA replication ( J:171665 )

• increase in DNA damage in interphase

growth/size/body

short upper incisors ( J:160175 )

• maxillary incisor and the diastema (the maxillary arch) are both abnormally short in the mutant

malocclusion ( J:160175 )

short snout ( J:160175 )

• decreased nose length

short ears ( J:160175 )

• short pinnae

decreased body size ( J:160175 )

decreased body weight ( J:160175 )

reproductive system

reduced female fertility ( J:160175 )

♀

vision/eye

shallow orbits ( J:160175 )

exophthalmos ( J:160175 )

ocular hypotelorism ( J:160175 )

integument

abnormal coat/hair pigmentation ( J:160175 )

• turns gray around 12 weeks of age

sparse hair ( J:160175 )

rough coat ( J:160175 )

• scruffy coat

flaky skin ( J:160175 )

homeostasis/metabolism

abnormal DNA replication ( J:171665 )

• increase in DNA damage in interphase

increased circulating phosphate level ( J:188496 )

• females exhibit a lower calcium/phosphorus ratio due to an increase of phosphorus rather than a decrease in calcium

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
otitis media		DOID:10754		J:188496
progeria		DOID:3911	OMIM:176670	J:171665