Phenotypes Associated with This Genotype

Genotype
MGI:3613050

• Allelic Composition: Dhcr7^tm1Fdp/Dhcr7^tm1Fdp
• Genetic Background: involves: 129S4/SvJae

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

mortality/aging

neonatal lethality, complete penetrance ( J:68084 )

• homozygotes die during their first day of life, most probably as a result of their failure to feed

behavior/neurological

absent gastric milk in neonates ( J:68084 )

abnormal suckling behavior ( J:68084 )

• homozygous mutant pups fail to suckle, as shown by absence of milk in their stomachs

no swallowing reflex ( J:68084 )

• hand-fed mutant pups are able to swallow formula; however, their swallowing movements lack the typical rhythmic sucking/swallowing pattern observed in wild-type pups

weakness ( J:68084 )

• mutant pups exhibit general weakness in the absence of gross limb, skeletal, renal, adrenal or CNS abnormalities

decreased locomotor activity ( J:68084 )

• mutant pups exhibit hypotonia and decreased movement in the absence of gross limb or skeletal malformations

• hypotonia is already evident at birth and does not appear to be secondary to lack of feeding

abnormal vocalization ( J:68084 )

• mutant newborns never vocalize alarm

homeostasis/metabolism

cyanosis ( J:68084 )

• mutant newborns with no nasal openings display cyanotic episodes consistent with obligate nasal breathing

abnormal cholesterol homeostasis ( J:68084 , J:165301 )

• mutant pups display a 1678-fold increase in serum 7-dehydrocholesterol (7-DHC) levels relative to wild-type pups; in addition, tissue 7-DHC levels are elevated 250-, 265-, 250-, 791- and 2003-fold in cortex, midbrain, kidney, liver and muscle, respectively (J:68084)

• 8-Dehydrocholesterol (an isomer of 7-DHC) is also markedly elevated in serum and similar tissue samples (J:68084)

• 7-dehydrodesmosterol (7-DHD) is accumulated in brain whereas desmosterol levels are markedly reduced in the cortex and midbrain of mutant pups (J:68084)

• 1-day old mice exhibit a striking localization of residual 7-dehydrocholesterol and cholesterol in the cerebellum and brainstem compared to wild-type mice that show diffuse cholesterol throughout the cerebellum, however normal localization of sterol metabolites is seen at E16-19 (J:165301)

• 7-dehydrocholesterol levels are about 8-fold higher in the cerebellum and brainstem than in controls (J:165301)

decreased cholesterol level ( J:68084 )

• mutant pups exhibit significantly reduced cholesterol levels in serum, cortex, midbrain, kidney, liver and muscle relative to wild-type pups

craniofacial

palatal shelves fail to meet at midline ( J:68084 )

• 9% of mutant pups exhibit a cleft palate characterized by elevation of the palatal shelves but failure of the secondary palate to close in the midline

abnormal nasal cavity morphology ( J:68084 )

• 30% of mutant pups retain a nasal plug in an otherwise normally formed nose

• 9% of mutant pups lack an identifiable nasal opening

growth/size/body

palatal shelves fail to meet at midline ( J:68084 )

• 9% of mutant pups exhibit a cleft palate characterized by elevation of the palatal shelves but failure of the secondary palate to close in the midline

abnormal nasal cavity morphology ( J:68084 )

• 30% of mutant pups retain a nasal plug in an otherwise normally formed nose

• 9% of mutant pups lack an identifiable nasal opening

decreased birth weight ( J:68084 )

• at birth, the average weight for mutant pups is 1.11 0.10 g vs 1.44 0.18 g for wild-type pups

fetal growth retardation ( J:68084 )

• homozygotes exhibit intra-uterine growth retardation which becomes more pronounced during the last 2 days of gestation

respiratory system

abnormal nasal cavity morphology ( J:68084 )

• 30% of mutant pups retain a nasal plug in an otherwise normally formed nose

• 9% of mutant pups lack an identifiable nasal opening

atelectasis ( J:68084 )

• mutant lungs display diffuse alveolar atelectasis

aspiration ( J:68084 )

• hand-feeding of mutant pups is precluded by aspiration, with dye-labeled formula staining the trachea, bronchi and lung parenchyma; however, no pharynx or trachea malformations are observed

nervous system

abnormal brain development ( J:165301 )

decreased brain size ( J:68084 )

• mutant brains are small, but brain weights are proportional to body weight and show no increased apoptosis

abnormal glutamate-mediated receptor currents ( J:68084 )

• mutant frontal cortex neurons show a normal response to the neurotransmitter gamma-amino-n-butyric acid (GABA); however, the response of these same neurons to exogenous glutamate (24 M) is significantly reduced

• impaired glutamate response does not appear to be due to altered expression of glutamate receptor subunits in mutant cortex

renal/urinary system

distended urinary bladder ( J:68084 )

• mutant pups display a dilated bladder with meconium detected in the colon

digestive/alimentary system

palatal shelves fail to meet at midline ( J:68084 )

• 9% of mutant pups exhibit a cleft palate characterized by elevation of the palatal shelves but failure of the secondary palate to close in the midline

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Smith-Lemli-Opitz syndrome		DOID:14692	OMIM:270400	J:68084 , J:165301