Phenotypes Associated with This Genotype

Genotype
MGI:2680800

• Allelic Composition: Clcn7^tm2Tjj/Clcn7^tm2Tjj
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

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

mortality/aging

postnatal lethality, incomplete penetrance ( J:67273 )

• from mating between heterozygous animals, the full 25% of mutant embryos were observed at E18

• however, only 16% existed at P7 and none survived past 6-7 weeks

growth/size/body

abnormal head morphology ( J:67273 )

• mice were described as having dysmorphic heads

failure of tooth eruption ( J:67273 )

• teeth were formed but did not erupt

decreased body size ( J:67273 )

• mice were smaller than littermates

• growth retardation became apparent during the second postnatal week and could not be prevent by feeding a liquid diet

skeleton

failure of tooth eruption ( J:67273 )

• teeth were formed but did not erupt

abnormal osteoclast morphology ( J:67273 , J:217031 )

• numerous abnormally elongated osteoclasts were present in the bones of mutant mice (J:67273)

• electron microscopy revealed only rudimentary ruffled border membranes (J:67273)

• 20% of osteoclasts completely lack a ruffled border, and only ~40% show a mature ruffled border, similar to what is observed in Clcn7^tm5.1Tjj homozygotes (J:217031)

abnormal osteoclast physiology ( J:67273 )

• osteoclasts were present in normal numbers but failed to resorb bone

abnormal bone marrow cavity morphology ( J:67273 )

• radiographs of the tibias revealed that the shortened bones lacked a marrow cavity

increased trabecular bone volume ( J:217031 )

• mice show increased bone volume fraction of proximal tibia metaphyseal trabecular bone, similar to that observed in Clcn7^tm5.1Tjj homozygotes

increased osteoblast cell number ( J:67273 )

• an increase in the number of osteoblasts were observed due to the enlarged surface of osteopetrotic bones

osteopetrosis ( J:67273 , J:217031 )

• the ratio of total bone volume to trabecular volume was increased about 7-fold in mutants mice at day P42 (J:67273)

• at 3 weeks of age, mice exhibit severe osteopetrosis (of tibiae), similar to that observed in Clcn7^tm5.1Tjj homozygotes (J:217031)

abnormal bone ossification ( J:67273 )

• subtle changes in bone morphology were observable at E16 at sites of beginning mineralization

limbs/digits/tail

short limbs ( J:67273 )

• radiographs of the tibias revealed that the shortened bones lacked a marrow cavity

craniofacial

failure of tooth eruption ( J:67273 )

• teeth were formed but did not erupt

pigmentation

abnormal coat/hair pigmentation ( J:217031 )

• mice display gray fur on an agouti background

abnormal hair shaft melanin granule distribution ( J:217031 )

• pheomelanin granules are clumped and reduced in the yellow band, whereas eumelanin granules are unchanged in the dark hair shafts

vision/eye

optic nerve degeneration ( J:67273 )

• optic nerve degeneration noted as beginning at P14

• ganglion cells were only mildly reduced at P28, suggesting that degeneration of the optic nerve and the retina are independent events

retina degeneration ( J:67273 , J:217031 )

• severe degeneration of photoreceptors beginning around P15 (J:67273)

• only a few photoreceptor cells remained at P28 (J:67273)

• at 4 weeks of age, mice exhibit degeneration of photoreceptor cells in the outer nuclear layer (ONL) and outer and inner segment, unlike wild-type controls or Clcn7^tm5.1Tjj homozygotes (J:217031)

nervous system

optic nerve degeneration ( J:67273 )

• optic nerve degeneration noted as beginning at P14

• ganglion cells were only mildly reduced at P28, suggesting that degeneration of the optic nerve and the retina are independent events

cellular

abnormal autophagy ( J:217031 )

• at 3 weeks of age, the autophagic marker LC3-II is significantly increased in the brain, unlike in wild-type controls or Clcn7^tm5.1Tjj homozygotes

homeostasis/metabolism

abnormal autophagy ( J:217031 )

• at 3 weeks of age, the autophagic marker LC3-II is significantly increased in the brain, unlike in wild-type controls or Clcn7^tm5.1Tjj homozygotes

hematopoietic system

abnormal osteoclast morphology ( J:67273 , J:217031 )

• numerous abnormally elongated osteoclasts were present in the bones of mutant mice (J:67273)

• electron microscopy revealed only rudimentary ruffled border membranes (J:67273)

• 20% of osteoclasts completely lack a ruffled border, and only ~40% show a mature ruffled border, similar to what is observed in Clcn7^tm5.1Tjj homozygotes (J:217031)

abnormal osteoclast physiology ( J:67273 )

• osteoclasts were present in normal numbers but failed to resorb bone

immune system

abnormal osteoclast morphology ( J:67273 , J:217031 )

• numerous abnormally elongated osteoclasts were present in the bones of mutant mice (J:67273)

• electron microscopy revealed only rudimentary ruffled border membranes (J:67273)

• 20% of osteoclasts completely lack a ruffled border, and only ~40% show a mature ruffled border, similar to what is observed in Clcn7^tm5.1Tjj homozygotes (J:217031)

abnormal osteoclast physiology ( J:67273 )

• osteoclasts were present in normal numbers but failed to resorb bone

integument

abnormal coat/hair pigmentation ( J:217031 )

• mice display gray fur on an agouti background

abnormal hair shaft melanin granule distribution ( J:217031 )

• pheomelanin granules are clumped and reduced in the yellow band, whereas eumelanin granules are unchanged in the dark hair shafts

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive osteopetrosis 4		DOID:0110944	OMIM:611490	J:67273