Phenotypes Associated with This Genotype

Genotype
MGI:3624035

• Allelic Composition: Mpv17/Mpv17
• Genetic Background: CFW-Mpv17/J

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

mortality/aging

premature death ( J:10661 , J:27358 , J:62419 , J:143355 )

• death between 2 and 9 months of age (J:10661)

• homozygotes are fertile and live long enough to reproduce (J:27358)

• survival to 52 weeks of age has been reported (J:62419)

• median life span is 645 days unlike in wild-type mice that survive longer (J:143355)

growth/size/body

decreased body weight ( J:143355 )

• after 1 year of age

cachexia ( J:10661 )

• weight loss associated with death

increased kidney weight ( J:62419 )

• increased kidney weight at 52 weeks of age

behavior/neurological

decreased locomotor activity ( J:10661 )

• become inactive prior to death

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:143355 )

N • unlike human patients with the hepatocerebral form of mitochondrial DNA depletion syndrome, mice fail to exhibit hypoglycemia or abnormal glucose tolerance

abnormal blood homeostasis ( J:10661 )

increased circulating creatinine level ( J:10661 )

• at 6-8 weeks of age

increased blood urea nitrogen level ( J:10661 )

• at 6-8 weeks of age

increased circulating lactate level ( J:143355 )

• beginning at 5 months, lactate levels are moderately higher than in wild-type mice

increased circulating cholesterol level ( J:10661 )

• at 6-8 weeks of age

increased circulating alanine transaminase level ( J:143355 )

• beginning at 5 months

increased circulating aspartate transaminase level ( J:143355 )

• beginning at 5 months

increased circulating creatine kinase level ( J:143355 )

• beginning at 5 months, serum creatine kinase levels are higher than in wild-type mice

decreased circulating serum albumin level ( J:10661 , J:62419 )

• at 6-8 weeks of age (J:10661)

increased urine sodium level ( J:59102 )

decreased urine osmolality ( J:59102 )

increased urine protein level ( J:10661 , J:108252 , J:143355 )

• at 6-8 weeks of age (J:10661)

• at 18 months without changes in the creatinine and urea serum levels (J:143355)

albuminuria ( J:62419 , J:108252 )

• evident at 8 weeks of age (J:62419)

• 95% of proteinuria due to albuminuria (J:108252)

hematopoietic system

anemia ( J:10661 )

• severe normocytic and normochromic anemia seen between 2 and 6 months of age

decreased erythrocyte cell number ( J:10661 )

• reduced RBC count at 6-8 weeks of age

decreased hemoglobin content ( J:10661 )

• reduced hemoglobin levels at 6-8 weeks of age

renal/urinary system

increased kidney weight ( J:62419 )

• increased kidney weight at 52 weeks of age

fused podocyte foot processes ( J:10661 )

• early fusion of foot processes in glomerular visceral epithelial cells

• eventual diffuse fusion of foot processes and vacuolation of cell cytoplasm

podocyte foot process effacement ( J:108252 )

• almost complete flattening of the foot processes at 180 days

abnormal renal glomerulus morphology ( J:108252 , J:143355 )

• 2-fold increase in reactive oxygen species (J:108252)

• 2.5-fold increase in lipid peroxidation adducts (J:108252)

• the amount of mitochondrial DNA in glomeruli at 6 months and 2 years is decreased compared to in wild-type mice (J:143355)

abnormal glomerular capillary morphology ( J:10661 )

• capillaries collapse

expanded mesangial matrix ( J:108252 )

• segmental mesangial sclerosis at 50 days of age

cortical renal glomerulopathies ( J:10661 , J:108252 )

• glomeruli become enlarged and capillaries collapse (J:10661)

• glomeruli become occluded with hyaline material (J:10661)

• enlargement slight at 50 days of age (J:108252)

glomerulosclerosis ( J:10661 , J:143355 )

• glomeruli eventually become totally obliterated by hyaline masses (J:10661)

• at 18 months, mice exhibit focal segmental glomerulosclerosis that by 2 years of age develops into frank degenerative changes of the glomeruli unlike in wild-type mice (J:143355)

renal glomerulus hypertrophy ( J:10661 , J:108252 )

• glomeruli become enlarged (J:10661)

• enlargement slight at 50 days of age (J:108252)

renal interstitial fibrosis ( J:143355 )

• at 2 years of age

abnormal renal tubule morphology ( J:108252 )

• hyaline and scarred segmental lesions at 180 days

dilated renal tubule ( J:10661 )

• microcystic dilation of renal tubules

kidney degeneration ( J:143355 )

• at 2 years of age, degenerative changes in the glomeruli are accompanied by degenerative abnormalities in the tubular system, with dilation and formation of pseudocysts, parenchymal loss, and interstitial fibrosis unlike in wild-type mice

• at 2 years, kidney mitochondrial DNA content is reduced 47% compared to in wild-type mice

abnormal renal/urinary system physiology ( J:59102 )

increased urine sodium level ( J:59102 )

decreased urine osmolality ( J:59102 )

increased urine protein level ( J:10661 , J:108252 , J:143355 )

• at 6-8 weeks of age (J:10661)

• at 18 months without changes in the creatinine and urea serum levels (J:143355)

albuminuria ( J:62419 , J:108252 )

• evident at 8 weeks of age (J:62419)

• 95% of proteinuria due to albuminuria (J:108252)

kidney failure ( J:48662 )

polyuria ( J:59102 )

• increased urinary volume

cardiovascular system

abnormal glomerular capillary morphology ( J:10661 )

• capillaries collapse

abnormal liver sinusoid morphology ( J:143355 )

• beginning at 5 months, sinusoidal spaces collapse unlike in wild-type mice

increased heart rate ( J:59102 )

hypertension ( J:59102 )

• significant hypertension

hearing/vestibular/ear

abnormal cochlea morphology ( J:48653 )

abnormal scala media morphology ( J:48653 )

cochlear outer hair cell degeneration ( J:48662 )

• pronounced OHC loss at 2 months of age

organ of Corti degeneration ( J:48653 , J:48662 )

• severe degeneration of the organ of Corti by 7 months (J:48662)

spiral ligament degeneration ( J:48653 , J:48662 )

• severe degeneration of the spiral ligament by 7 months (J:48662)

stria vascularis degeneration ( J:48653 , J:48662 )

• moderate degenerative alterations at 2 months of age (J:48662)

• severe degeneration of the stria vascularis by 7 months (J:48662)

abnormal auditory brainstem response ( J:48661 )

• at 2 months of age, poor brainstem evoked responses are obtained at 1-32 kHz

increased or absent threshold for auditory brainstem response ( J:48661 )

• by 7 months of age, no brainstem evoked responses can be elicited

sensorineural hearing loss ( J:48661 , J:48662 )

• severe sensorineural hearing loss as early as 2 months after birth (J:48661)

nervous system

cochlear outer hair cell degeneration ( J:48662 )

• pronounced OHC loss at 2 months of age

cochlear ganglion degeneration ( J:48662 )

• marked loss of spiral ganglion cells by 7 months

cochlear ganglion hypoplasia ( J:48653 )

• loss of cochlear neurons

adipose tissue

decreased subcutaneous adipose tissue amount ( J:143355 )

• at 2 years

cellular

cellular phenotype ( J:143355 )

N • despite defects in mitochondria morphology, mice exhibit normal mitochondrial response to hypothermia

decreased mitochondrial DNA content ( J:143355 )

• the mitochondrial DNA content in the liver and muscle is very low compared to in wild-type mice

• proliferating and non-proliferating mouse embryonic fibroblast exhibit a decrease in mitochondrial DNA over time compared to an increase in wild-type cells

• the amount of mitochondrial DNA in glomeruli at 6 months and 2 years is decreased compared to in wild-type mice

• at 2 years, kidney mitochondrial DNA content is reduced 47% compared to in wild-type mice

• however, mitochondrial DNA content in the brain is normal

decreased hepatocyte mitochondrial DNA content ( J:143355 )

decreased muscle fiber mitochondrial DNA content ( J:143355 )

abnormal mitochondrial crista morphology ( J:143355 )

• older mice exhibit disappearance of internal cristae unlike in wild-type mice

dilated mitochondrion ( J:143355 )

• older mice exhibit mitochondrial ballooning unlike in wild-type mice

endocrine/exocrine glands

abnormal sebaceous gland morphology ( J:143355 )

• at 2 years, sebaceous gland and annexa size and numbers are decreased compared to in wild-type mice

small sebaceous gland ( J:143355 )

• at 2 years

liver/biliary system

liver/biliary system phenotype ( J:143355 )

N • despite abnormal liver morphology, mice do not exhibit increased susceptibility to chemically-induced liver damage using valporic acid

abnormal liver lobule morphology ( J:143355 )

• beginning at 5 months, scattered degeneration of discrete areas of hepatic lobules occurs unlike in wild-type mice

abnormal liver sinusoid morphology ( J:143355 )

• beginning at 5 months, sinusoidal spaces collapse unlike in wild-type mice

abnormal hepatocyte morphology ( J:143355 )

• beginning at 5 months, hepatocytes are swollen with shrunken nuclei unlike wild-type cells

decreased hepatocyte mitochondrial DNA content ( J:143355 )

abnormal portal triad morphology ( J:143355 )

• beginning at 5 months, inflammatory infiltrate concentrates on the portal triads unlike in wild-type mice

pigmentation

abnormal coat/hair pigmentation ( J:143355 )

• mice develop gray coat color 5 to 6 months after birth unlike wild-type mice

integument

decreased subcutaneous adipose tissue amount ( J:143355 )

• at 2 years

abnormal sebaceous gland morphology ( J:143355 )

• at 2 years, sebaceous gland and annexa size and numbers are decreased compared to in wild-type mice

small sebaceous gland ( J:143355 )

• at 2 years

abnormal coat/hair pigmentation ( J:143355 )

• mice develop gray coat color 5 to 6 months after birth unlike wild-type mice

abnormal hypodermis muscle layer morphology ( J:143355 )

• at 2 years of age, mice exhibit disorganization of the muscle layer

decreased hair follicle number ( J:143355 )

• at 2 years, hair follicles are hypotrophic compared to in wild-type mice

abnormal skin morphology ( J:143355 )

• at 2 years, mice exhibit severe atrophy of the skin layers, with thinning of the epidermis unlike in wild-type mice

thin epidermis ( J:143355 )

• at 2 years

thin skin ( J:143355 )

• late-onset

muscle

decreased muscle fiber mitochondrial DNA content ( J:143355 )

abnormal hypodermis muscle layer morphology ( J:143355 )

• at 2 years of age, mice exhibit disorganization of the muscle layer

skeleton

spiral ligament degeneration ( J:48653 , J:48662 )

• severe degeneration of the spiral ligament by 7 months (J:48662)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive Alport syndrome		DOID:0110033	OMIM:203780	J:48653
mitochondrial DNA depletion syndrome 3		DOID:0080121	OMIM:251880	J:143355
nephrotic syndrome		DOID:1184		J:10661 , J:108252