Phenotypes associated with this allele

• Allele Symbol: Atr^tm1Ofc
• Allele Name: targeted mutation 1, Oscar Fernandez-Capetillo
• Allele ID: MGI:4355008
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Atr^tm1Ofc/Atr^tm1Ofc	involves: 129 * C57BL/6	MGI:7266825
hm2	Atr^tm1Ofc/Atr^tm1Ofc	Not Specified	MGI:4355020
cx3	Atr^tm1Ofc/Atr^tm1Ofc Trp53^tm1Tyj/Trp53^tm1Tyj	involves: 129S2/SvPas	MGI:4355022

Genotype
MGI:7266825

hm1

• Allelic Composition: Atr^tm1Ofc/Atr^tm1Ofc
• Genetic Background: involves: 129 * C57BL/6

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

reproductive system

increased granulosa cell apoptosis ( J:307570 )

♀ • prepubertal and adult ovaries show a 5-fold and a 9-fold increase, respectively, in granulosa cell apoptosis in small secondary follicles

♀ • however, the rate of granulosa cell apoptosis is not significantly altered in primary follicles at either age

decreased granulosa cell proliferation ( J:307570 )

♀ • adult ovaries show a significantly reduced proportion of EdU+ granulosa cells in primary follicles

increased granulosa cell proliferation ( J:307570 )

♀ • both prepubertal and adult ovaries show a significantly increased proportion of EdU+ granulosa cells in small secondary follicles

abnormal ovarian follicle morphology ( J:307570 )

♀ • growing follicles are smaller than those found in control ovaries

decreased primary ovarian follicle number ( J:307570 )

♀ • adult ovaries show a significant reduction in primary follicles

increased primordial ovarian follicle number ( J:307570 )

♀ • adult ovaries show a 3-fold increase in the number of primordial follicles

decreased secondary ovarian follicle number ( J:307570 )

♀ • adult ovaries show a significant reduction in secondary follicles

♀ • however, the number of antral follicles is normal

impaired ovarian folliculogenesis ( J:307570 )

♀ • adult females show altered folliculogenesis progression resulting in a reduction of growing follicles

♀ • adult ovaries show significantly reduced granulosa cell proliferation in primary follicles but increased granulosa cell proliferation in small secondary follicles

♀ • both prepubertal and adult ovaries show a significantly higher proportion of TUNEL+ apoptotic granulosa and theca cells in small secondary follicles than control ovaries

♀ • however, no differences in the proportion of EdU+ theca cells are seen in P21 or adult mice

abnormal female meiosis ( J:307570 )

♀ • oocytes show a significantly greater number of bivalents lacking MLH1 foci than wild-type oocytes at pachynema (3.9% versus 2.1%) but no significant differences at diplonema, suggesting a delay in crossover formation rather than an inability to form crossovers

♀ • however, meiotic prophase progression is grossly unaffected

cellular

increased granulosa cell apoptosis ( J:307570 )

♀ • prepubertal and adult ovaries show a 5-fold and a 9-fold increase, respectively, in granulosa cell apoptosis in small secondary follicles

♀ • however, the rate of granulosa cell apoptosis is not significantly altered in primary follicles at either age

decreased granulosa cell proliferation ( J:307570 )

♀ • adult ovaries show a significantly reduced proportion of EdU+ granulosa cells in primary follicles

increased granulosa cell proliferation ( J:307570 )

♀ • both prepubertal and adult ovaries show a significantly increased proportion of EdU+ granulosa cells in small secondary follicles

endocrine/exocrine glands

increased granulosa cell apoptosis ( J:307570 )

♀ • prepubertal and adult ovaries show a 5-fold and a 9-fold increase, respectively, in granulosa cell apoptosis in small secondary follicles

♀ • however, the rate of granulosa cell apoptosis is not significantly altered in primary follicles at either age

decreased granulosa cell proliferation ( J:307570 )

♀ • adult ovaries show a significantly reduced proportion of EdU+ granulosa cells in primary follicles

increased granulosa cell proliferation ( J:307570 )

♀ • both prepubertal and adult ovaries show a significantly increased proportion of EdU+ granulosa cells in small secondary follicles

abnormal ovarian follicle morphology ( J:307570 )

♀ • growing follicles are smaller than those found in control ovaries

decreased primary ovarian follicle number ( J:307570 )

♀ • adult ovaries show a significant reduction in primary follicles

increased primordial ovarian follicle number ( J:307570 )

♀ • adult ovaries show a 3-fold increase in the number of primordial follicles

decreased secondary ovarian follicle number ( J:307570 )

♀ • adult ovaries show a significant reduction in secondary follicles

♀ • however, the number of antral follicles is normal

impaired ovarian folliculogenesis ( J:307570 )

♀ • adult females show altered folliculogenesis progression resulting in a reduction of growing follicles

♀ • adult ovaries show significantly reduced granulosa cell proliferation in primary follicles but increased granulosa cell proliferation in small secondary follicles

♀ • both prepubertal and adult ovaries show a significantly higher proportion of TUNEL+ apoptotic granulosa and theca cells in small secondary follicles than control ovaries

♀ • however, no differences in the proportion of EdU+ theca cells are seen in P21 or adult mice

Genotype
MGI:4355020

hm2

• Allelic Composition: Atr^tm1Ofc/Atr^tm1Ofc
• Genetic Background: Not Specified

mortality/aging

premature death ( J:151542 )

• mice by before 6 months of age

prenatal lethality, incomplete penetrance ( J:151542 )

• fewer than expected mice are born

premature aging ( J:151542 )

• mice exhibit signs of premature aging such as cachexia, graying hair, kyphosis, osteoporosis, accumulation of fat in the bone marrow, decreased hair follicles and thinner epidermis prior to premature death at less than 6 months of age

reproductive system

abnormal primary ovarian follicle morphology ( J:151542 )

♀ • degenerating in newborn mice

decreased ovary weight ( J:151542 )

♀

decreased testis weight ( J:151542 )

♂

abnormal oogenesis ( J:151542 )

♀ • impaired

absent oocytes ( J:151542 )

♀

cellular

absent oocytes ( J:151542 )

♀

abnormal cell cycle ( J:151542 )

• more mouse embryonic fibroblasts accumulate at G2 than wild-type cells

increased cellular sensitivity to methylmethanesulfonate ( J:151542 )

• in mouse embryonic fibroblasts

increased cellular sensitivity to ultraviolet irradiation ( J:151542 )

• in mouse embryonic fibroblasts

increased apoptosis ( J:151542 )

• embryonic and newborn brains exhibit apoptosis and replicative stress in replicating areas unlike in wild-type mice

increased fibroblast apoptosis ( J:151542 )

• treatment of mouse embryonic fibroblasts with PIKK inhibitors increased apoptosis compared to similarly treated wild-type cells

early cellular replicative senescence ( J:151542 )

• in mouse embryonic fibroblasts

abnormal DNA replication ( J:151542 )

• mouse embryonic fibroblasts and E13.5 whole embryos exhibit replicative stress-initiated DNA damage response unlike wild-type cells

• adult tissues exhibit a marginal increase in replicative stress-initiated DNA damage response

• embryonic and newborn brains exhibit apoptosis and replicative stress in replicating areas unlike in wild-type mice

spontaneous chromosome breakage ( J:151542 )

• at metaphase in mouse embryonic fibroblasts unlike in wild-type cells

skeleton

abnormal cranial suture morphology ( J:151542 )

• indentations of the sutures between the cranial bones are reduced compared to in wild-type mice

abnormal fontanelle morphology ( J:151542 )

• 6 of 9 mice exhibit a deficient closure of the fontanelles unlike in wild-type mice

malocclusion ( J:151542 )

micrognathia ( J:151542 )

kyphosis ( J:151542 )

• at 2 months of age

abnormal bone marrow morphology ( J:151542 )

• at 2 months, mice exhibit an accumulation of fat in the bone marrow unlike wild-type mice

osteoporosis ( J:151542 )

growth/size/body

malocclusion ( J:151542 )

sloping forehead ( J:151542 )

• receding forehead

abnormal nose morphology ( J:151542 )

• protruding

abnormal head shape ( J:151542 )

• mice exhibit dysmorphic heads with receding forehead compared with wild-type mice

decreased body weight ( J:151542 )

cachexia ( J:151542 )

small thoracic cavity ( J:151542 )

abnormal head size ( J:151542 )

• at 3 months, head circumference is reduced compared to in wild-type mice

microcephaly ( J:151542 )

decreased body length ( J:151542 )

proportional dwarf ( J:151542 )

• severe

nervous system

abnormal brain morphology ( J:151542 )

• mice develop brain cysts unlike wild-type mice

decreased brain size ( J:151542 )

decreased brain weight ( J:151542 )

absent corpus callosum ( J:151542 )

abnormal astrocyte morphology ( J:151542 )

• at 6 weeks, mice exhibit severe loss of astrocytes at the corpus callosum unlike in wild-type mice

homeostasis/metabolism

abnormal DNA replication ( J:151542 )

• mouse embryonic fibroblasts and E13.5 whole embryos exhibit replicative stress-initiated DNA damage response unlike wild-type cells

• adult tissues exhibit a marginal increase in replicative stress-initiated DNA damage response

• embryonic and newborn brains exhibit apoptosis and replicative stress in replicating areas unlike in wild-type mice

immune system

decreased thymus weight ( J:151542 )

• thymus weight is decreased and not restored by transfer of wild-type bone marrow

decreased spleen weight ( J:151542 )

liver/biliary system

decreased liver weight ( J:151542 )

embryo

abnormal placenta morphology ( J:151542 )

• placentas exhibit an accumulation of necrotic areas and an overall loss of cellularity unlike wild-type placenta

respiratory system

abnormal nose morphology ( J:151542 )

• protruding

decreased lung weight ( J:151542 )

hematopoietic system

decreased thymus weight ( J:151542 )

• thymus weight is decreased and not restored by transfer of wild-type bone marrow

decreased bone marrow cell number ( J:151542 )

pancytopenia ( J:151542 )

abnormal hematopoietic stem cell morphology ( J:151542 )

• in young mice, the number of long-term hematopoietic stem cells is high while the number of multipotent progenitors is low compared to in wild-type mice

• when bone marrow cells are transplanted into irradiated mice reconstitution of the granulocyte population occurs but stem cell niches are compromised

decreased spleen weight ( J:151542 )

craniofacial

abnormal cranial suture morphology ( J:151542 )

• indentations of the sutures between the cranial bones are reduced compared to in wild-type mice

abnormal fontanelle morphology ( J:151542 )

• 6 of 9 mice exhibit a deficient closure of the fontanelles unlike in wild-type mice

malocclusion ( J:151542 )

micrognathia ( J:151542 )

sloping forehead ( J:151542 )

• receding forehead

abnormal nose morphology ( J:151542 )

• protruding

abnormal head shape ( J:151542 )

• mice exhibit dysmorphic heads with receding forehead compared with wild-type mice

endocrine/exocrine glands

decreased thymus weight ( J:151542 )

• thymus weight is decreased and not restored by transfer of wild-type bone marrow

abnormal primary ovarian follicle morphology ( J:151542 )

♀ • degenerating in newborn mice

decreased ovary weight ( J:151542 )

♀

decreased testis weight ( J:151542 )

♂

pigmentation

abnormal coat/hair pigmentation ( J:151542 )

• graying

integument

abnormal coat/hair pigmentation ( J:151542 )

• graying

decreased hair follicle number ( J:151542 )

thin epidermis ( J:151542 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Seckel syndrome		DOID:0050569	OMIM:PS210600	J:151542

Genotype
MGI:4355022

cx3

• Allelic Composition: Atr^tm1Ofc/Atr^tm1Ofc; Trp53^tm1Tyj/Trp53^tm1Tyj
• Genetic Background: involves: 129S2/SvPas

mortality/aging

premature death ( J:151542 )

• mice do not survive beyond 2 months

prenatal lethality, incomplete penetrance ( J:151542 )

• few mice are born

premature aging ( J:151542 )

• mice exhibit a more severe premature aging syndrome than in Atr^tm1Ofc homozygotes

skeleton

micrognathia ( J:151542 )

kyphosis ( J:151542 )

osteoporosis ( J:151542 )

growth/size/body

decreased body weight ( J:151542 )

small thoracic cavity ( J:151542 )

microcephaly ( J:151542 )

proportional dwarf ( J:151542 )

• more severe than in Atr^tm1Ofc homozygotes

cellular

increased embryonic tissue cell apoptosis ( J:151542 )

• apoptosis in the whole embryos is greater than in Atr^tm1Ofc homozygotes

abnormal DNA replication ( J:151542 )

• embryos exhibit replicative stress-initiated DNA damage response unlike wild-type mice

homeostasis/metabolism

abnormal DNA replication ( J:151542 )

• embryos exhibit replicative stress-initiated DNA damage response unlike wild-type mice

craniofacial

micrognathia ( J:151542 )

hematopoietic system

pancytopenia ( J:151542 )

embryo

increased embryonic tissue cell apoptosis ( J:151542 )

• apoptosis in the whole embryos is greater than in Atr^tm1Ofc homozygotes