Table 1.
Human Diseases Associated with Defects in the Replication Stress Response
| Human Disease | Etiology | Characteristics | |
|---|---|---|---|
| Affected Pathway | Defective Protein(s) |
||
| Aicardi-Goutieres syndrome (OMIM 610333, 610181, 610329, 225750, 612952) | Removal of ribonucleotides, RNA:DNA hybrids | RNase H2, TREX1, SAMHD1 | Neurological dysfunction, appearance of chilblains |
| Amyotrophic lateral sclerosis 4 (OMIM 602433) | Resolution of RNA:DNA hybrids, transcription termination | Senataxin | Childhood- or adolescent-onset degeneration of motor control |
| Ataxia-ocular apraxia 2 (OMIM 606002) | Adolescent-onset cerebellar ataxia | ||
| Ataxia-telangiectasia-like disease (OMIM 604391) | MRN complex; ATR/ATM activation | Mre11 | Neurodegeneration, ataxia |
| Bloom syndrome (OMIM 210900) | DNA remodeling, replication fork structure resolution | BLM | Premature aging, growth retardation, cancer predisposition |
| Cancer137 | Many | Many | Uncontrolled cell growth, leading to organ failure |
| Ciliopathies138 | Centrosome, primary cilia formation | CEP164, Nek8, Mre11, Znf423, Fan1 | Dysfunction or degeneration of organs, particularly kidney, retina, and brain |
| Congenital dyserythropoetic anemia, type 1 (OMIM 224120)127 | Histone deposition | CDAN1 | Anemia, skeletal abnormalities |
| Fanconi anemia44 | DNA inter-strand crosslink repair | FANC family of proteins | Heterogenous - bone marrow failure, skeletal defects, hypopigmentation, cancer predisposition |
| Replication fork protection | FANCD2, BRCA2 | ||
| Friedreich ataxia (OMIM 229300) | Trinucleotide repeat expansion | FXN | Neurodegeneration (ataxia, loss of coordination, loss of sensation) |
| Laminopathies139 | Nuclear envelope structure | Lamins | Premature aging |
| Meier-Gorlin syndrome (OMIM 224690) | Origin licensing, centrosome maintenance | ORC1, ORC4, ORC6, CDT1, CDC6 | Growth retardation, microcephaly |
| Nijmegen breakage syndrome (OMIM 251260) | MRN complex; ATR/ATM activation | Nbs1 | Microcephaly, growth retardation, cancer predisposition |
| Nijmegen breakage syndrome-like disorder (OMIM 613078) | MRN complex; ATR/ATM activation | Rad50 | Microcephaly, growth retardation, mental retardation |
| Rothmund-Thomson syndrome (OMIM 268400) | DNA remodeling, replication fork structure resolution | RecQL4 | Premature aging, growth retardation, cancer predisposition |
| Schimke immunoosseous dysplasia (OMIM 242900) | Replication fork stabilization and reversal; DNA reannealing | SMARCAL1 / HARP | Dwarfism, skeletal abnormalities, renal failure, and immunodeficiency |
| Seckel syndrome (OMIM 210600) | ATR signaling | ATR, ATRIP, CENPJ, CEP152, PCNT | Growth retardation, dwarfism, microcephaly, mental retardation |
| Spinocerebellar ataxia type 10 (OMIM 603516) | Trinucleotide repeat expansion | ATXN10 | Ataxia, seizures |
| Werner syndrome (OMIM 277700) | DNA remodeling, replication fork structure resolution | WRN | Premature aging, growth retardation, cancer predisposition |
| Wolf-Hirschhorn syndrome (OMIM 194190)125 | DNA damage response, Nucleosome deposition | NELF-A (WHS2), SLBP, MMSET (WHS1) | Growth retardation, mental retardation, seizures |
| Xeroderma pigmentosum – variant (OMIM 278750) | Translesion synthesis | Polymerase η | Cancer predisposition (especially skin cancer) |