Phenotypes Associated with This Genotype

Genotype
MGI:6394002

• Allelic Composition: Hmbs^tm1.1Rjde/Hmbs^tm1.1Rjde
• Genetic Background: involves: 129/Sv * C57BL/6

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

mortality/aging

premature death ( J:275245 )

• mice are born at near expected Mendelian ratios (22%) but only about 65% survive to adulthood

• about 90% of lethality occurs during P20-P30

• mice that survive beyond P30 are able to mate and have a normal lifespan

growth/size/body

decreased body size ( J:275245 )

• mice are smaller from infancy

decreased body weight ( J:275245 )

• gap in body weight widens with age

• mice remain lean throughout life

decreased body length ( J:275245 )

behavior/neurological

limb grasping ( J:275245 )

• mice show dystonic postures of their hind legs with self-clasping when hung by their tails

tremors ( J:275245 )

• mice exhibit intension tremors by P7

ataxia ( J:275245 )

• mice exhibit jerky, ataxic gait by P7

• ataxia becomes less apparent and mice are able to walk relatively normally after P30

impaired coordination ( J:275245 )

• rotarod preference is impaired at 2 months and progressively worsens with age

jerky movement ( J:275245 )

• mice exhibit jerky, ataxic gait by P7

decreased locomotor activity ( J:275245 )

• in a 3 min open field test at P9, P12, P15, and P21, mice show reduced number of boxes traveled

motor developmental delay ( J:275245 )

• mice show delayed and impaired performance for tasks requiring postural skills and complex motor coordination indicating developmental delay of motor skills

• however, mice show normal sensory development (ear twitch and auditory startle) and acquisition of early reflexes (grasping, surface and air righting)

• the ability to rear with or without support, sit without support and jump are delayed

• extinguishing of pivoting is delayed and mice often propel themselves using only their forelimbs, with their bellies on the ground

liver/biliary system

abnormal liver morphology ( J:275245 )

• total heme content in the liver is approximately 93% of wild-type levels

• however, hepatic heme saturation levels of tryptophan 2,3-dioxygenase are normal

hematopoietic system

increased erythrocyte protoporphyrin level ( J:275245 )

• erythrocyte porphyrin precursors are elevated, with ALA and PBG increased by 1.5 and 38-fold

• porphyrins, predominantly the uroporphrin I isomer, are elevated in erythrocytes and various tissues, including liver, kidney, and brain

homeostasis/metabolism

increased erythrocyte protoporphyrin level ( J:275245 )

• erythrocyte porphyrin precursors are elevated, with ALA and PBG increased by 1.5 and 38-fold

• porphyrins, predominantly the uroporphrin I isomer, are elevated in erythrocytes and various tissues, including liver, kidney, and brain

decreased hydroxymethylbilane synthase level ( J:275245 )

• mice show approximately 5-8% of wild-type hydroxymethylbilane synthase activities in erythrocytes and various tissues, including liver, kidney, heart and brain

• however, mice have normal complete blood count and are not anemic

porphyria ( J:275245 )

• plasma 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) are elevated about 7-fold and 134-fold, respectively

• ALA and PBG concentrations in the liver, kidney, heart, and spleen are elevated by 1.5- to 2.5-fold and 73- to 390-fold, respectively

• ALA and PBG levels are elevated in the CNS tissue, including the brain, the spinal cord, cerebral spinal fluid

• porphyrins, predominantly the uroporphrin I isomer, are elevated in various tissues, including liver, kidney, and brain

• mice are not readily inducible by porphyrinogenic factors including fasting, pregnenolone-16alpha-carbonitrile, phenobarbital, and phenobarbital with 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine

abnormal urine homeostasis ( J:275245 )

• mice exhibit porphrinuria

• urinary ALA and PBG are elevated about 5-fold and 60-fold, respectively

• urinary uroporphyrin I and III are elevated by 15- and about 50-fold, respectively

• however, coproporphyrin I and III isomers are only slightly elevated or normal

nervous system

abnormal brain morphology ( J:275245 )

• total heme content in the brain is approximately 80% of wild-type levels

decreased myelin sheath amount ( J:275245 )

• overall myelin volume in the brain is reduced by about 30% at 3 months of age, and when normalized for brain volume, is decreased by about 25%

abnormal myelination ( J:275245 )

• mice have barely detectable levels of MBP at P14 and do not express high levels until P15 indicating that CNS myelination is slightly delayed

• however, mice exhibit normal CNS and peripheral motor nerve histology

renal/urinary system

abnormal urine homeostasis ( J:275245 )

• mice exhibit porphrinuria

• urinary ALA and PBG are elevated about 5-fold and 60-fold, respectively

• urinary uroporphyrin I and III are elevated by 15- and about 50-fold, respectively

• however, coproporphyrin I and III isomers are only slightly elevated or normal

vision/eye

delayed eyelid opening ( J:275245 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
acute intermittent porphyria		DOID:3890	OMIM:176000	J:275245