Table 2.
Summary of key murine models of inherited bone marrow failure syndrome
| Disease phenotype/Gene name | Affected systems | References |
|---|---|---|
| FA/Fanca | Homozygotes displayed FA‐like phenotypes including growth retardation, microphthalmia, craniofacial malformations and hypogonadism. Homozygous females demonstrate premature reproductive senescence and an increased incidence of ovarian cysts. Homozygous males exhibit an elevated frequency of mis‐paired meiotic chromosomes and increased apoptosis in germ cells, implicating a role for Fanca in meiotic recombination. Fancc‐/‐ Fanca‐/‐ display the same phenotype as the single mutants suggesting that these two genes are epistatic. | 28, 29 |
| FA/Fancc | Homozygotes do not show developmental abnormalities or hematological defects till 9‐12 months of age. Male and female mutant mice have reduced numbers of germ cells and females have markedly impaired fertility. The CFC capacity of hematopoietic progenitors is abnormal and the cells are hypersensitive to gamma‐interferon. Fancc‐/‐Tert‐/‐ double mutant mice have exacerbate telomere attrition when murine bone marrow cells experience high cell turnover after serial transplantation and increase in the incidence of telomere sister chromatid exchange. Fancc‐/‐Fancg‐/‐ double‐mutant mice develop spontaneous hematologic sequelae, including bone marrow failure, acute myeloid leukemia, myelodysplasia and complex random chromosomal abnormalities. | 30, 31 |
| FA/Fancd1 | Homozygous null mutants are embryonic lethal with abnormalities including growth retardation, neural tube defects, and mesoderm abnormalities; conditional mutations cause genetic instability and enhanced tumor formation; mutants with truncated BRCA2 protein survive, are small, infertile, show improper tissue differentiation and develop lymphomas and carcinomas | 32 |
| FA/Fancd2 | Homozygous mutant mice exhibit meiotic defects and germ cell loss. In addition, mutant mice display perinatal lethality, susceptibility to epithelial cancer and microphthalmia. Homozygous mice have smaller hematopoietic stem cell pool and reduced lymphoid progenitor frequency. Fancd2‐/‐Aldh2‐/‐ double homozygous mice are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double‐deficient mice rapidly precipitates bone marrow failure and spontaneously developed acute leukemia. Aged Aldh2‐/‐Fancd2‐/‐ mutant mice which do not develop leukemia, spontaneously develop aplastic anemia, with concomitant accumulation of damaged DNA within the hematopoietic stem and progenitor cell pool. | [33‐35] |
| FA/Fancg | Females and males homozygous for targeted null mutations exhibit hypogonadism and reduced fertility. Cytogenetic analysis shows somatic chromosome aberrations occurrence at a higher spontaneous rate. Cells are also more sensitive to mitomycin C. | 36 |
| FA/Fanci | These mice show craniofacial, vision, and eye abnormalities. | 37 |
| FA/Fancn | Homozygotes display embryonic lethality with impaired inner cell mass proliferation, impaired gastrulation, absence of the amnion, somites and tail bud, and general improper organogenesis. | 38 |
| FA/Fancm | Homozygotes exhibit reduced female transmission, hypogonadism, premature death and increased incidence of tumors. | 39 |
| FA/Fancp | Homozygotes display exhibit preweaning lethality, reduced fertility, abnormal eye morphology, abnormal skeletal morphology, hydrocephalus, chromosomal instability, early cellular replicative senescence and abnormal lymphopoeisis. Mutant mice are characterized by blood cytopenia, premature senescence, accumulation of damaged chromosomes and hypersensitivity to DNA cross linking agents. | 40 |
| FA/Fanco | Mice homozygous for a null mutation display embryonic lethality. Mice carrying a null and a hypomorphic allele have partial penetrance of male and female infertility due to defects in meiosis. | 41 |
| FA/Fancs | Homozygous null mutants are embryonic lethal with abnormalities including growth retardation, neural tube defects, and mesoderm abnormalities; conditional mutations cause genetic instability and enhanced tumor formation; mutants with truncated BRCA1 protein survive, have a kinky tail, pigmentation anomalies, male infertility and increased tumor incidence. | 42 |
| DKC/Dkc1 | Early generation male mice hemizygous for a hypomorphic allele exhibit bone marrow failure, dyskeratosis, extramedullary hematopoieis, splenomegaly, lung and kidney abnormalities, increased tumor incidence, altered ribosome function. Decreased telomere length is noted only in later generations. | 43 |
| DKC/Tert | In spite of impaired telomerase function, homozygous mutant mice are overtly normal in early generations. Impaired fertility has been reported in later generations for homozygotes of at least one knockout allele. Homozygous Tert mice display short dysfunctional telomeres and sustained increased DNA damage signaling and classical degenerative phenotypes upon successive generational mattings and advancing age. | 44 |
| DKC/Tr | Early generation mice homozygous for a null allele have intact telomeres and appear grossly unaffected and healthy, whereas late generation mutants exhibit premature death, shortened and dysfunctional telomeres, apoptotic and proliferative defects, infertility, and multi‐organ degenerative decline. Late‐generation animals exhibit defective spermatogenesis, with increased programmed cell death (apoptosis) and decreased proliferation in the testis. Proliferative capacity of hematopoietic cells in the bone marrow and spleen is also compromised. These progressively adverse effects coincide with substantial erosion of telomeres and fusion and loss of chromosomes. | 45 |
| DKC/Tinf2 | Targeted disruption of this gene results in embryonic lethality prior to E7.5 through a mechanism that is independent of telomerase function. Second and third generation heterozygotes develop mild pancytopenia, consistent with hematopoietic dysfunction in DKC, as well as diminished fecundity. | 46 |
| DKC/Rtel1 | Homozygous null mice display embryonic lethality with abnormal development of the neural tube, brain, heart, vasculature, placenta, and allantois and chromosomal abnormalities in differentiating cells. | 47 |
| DKC/Ctc1 | Mice homozygous for a targeted allele exhibit defective telomere replication that leads to stem cell exhaustion, bone marrow failure and premature death. | 48 |
| DBA/Rps6 | Conditional Rps6 mice using CD4‐Cre abolishes T cell development. | 49 |
| DBA/Rps7 | Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid‐ventral white spotting, and eye malformations. Rps7 mutants display overt malformations of the developing central nervous system and deficits in working memory; however they do not show anemia or hyperpigmentation. | 50 |
| DBA/Rps19 | Homozygous null embryos die prior to the formation of a blastocyst. Mice heterozygous for some point mutations show pigment defects affecting the feet and tail. However the heterozygotes show a normal development of the hematopoietic system. Heterozygous missense mutations of Rps19 show a mild macrocytic anemia reflecting the fact that mutations causes a hypomorphic allele rather than true happloinsufficiency. | 51 |
| DBA/Rps20 | Heterozygous missense mutations of Rps20 show a mild macrocytic anemia reflecting the fact that mutations causes a hypomorphic allele rather than true happloinsufficiency. | 52 |
| SDS/Sbds | Loss of Sbds gene results in early embryonic lethality, with homozygotes showing histological abnormalities of the liver and accumulation of free cytoplasmic 40 S and 60 S subunits. Heterozygotes have a normal phenotype. | 53 |
| CAMT/Mpl | Mice homozygous for targeted mutations at this locus are unable to produce normal numbers of megakaryocytes and platelets and display HSC deficiencies that are not limited to megakaryocytic lineages. These mice also have increased concentrations of circulating TPO. | 54 |
| SCN/Ela2 | Homozygotes for a null allele show impaired neutrophil physiology, susceptibility to Gram (‐) bacterial infection, reduced sensitivity to xenobiotics and abnormal local Schwartzman responses. Homozygotes for a knock‐in allele show susceptibility to fungal infection and resistance to endotoxic shock. Heterozygous mice do not show neutropenia. | 55 |
| SCN/HAX1 | Mice homozygous for deletion of this gene fail to survive beyond 14 weeks of age. Apoptosis of neurons in the striatum and cerebellum occurs as does loss of lymphocytes and neutrophils. | 56 |
| SCN/Gfi1 | Homozygotes are severely neutropenic and accumulate immature monocytes in blood and bone marrow. Their myeloid precursors cannot differentiate into granulocytes upon stimulation with G‐CSF; however they can develop into macrophages. Conditional knockouts indicate defects in Th2 cell expansions and enhanced IFNγ production. | 57 |
| SCN/Wasp | Homozygous mutant females and hemizygous mutant males exhibit reduced numbers of peripheral blood lymphocytes and platelets, but increased numbers of neutrophils. | 58 |
| RS/Hoxa11 | Homozygotes for targeted null mutations exhibit homeotic transformations affecting thoracic and sacral vertebrae, and forelimb defects. Mutants are sterile due to malformed vas deferens and cryptorchism in males, and defective uteri in females. | 59 |
Abbreviations: CFC, colony‐forming cell; G‐CSF, granulocyte colony stimulating factor; FA, Fanconi anemia; HSCs, hematopoietic stem cells; IFNγ, interferon γ; TPO, thrombopoietin.