A variety of other syndromes including Fanconi anemia (FA), Werner syndrome (WS), Bloom syndrome (BLM) and Rothmund Thomson syndrome (RTS) also result from DNA repair defects (). FA can result from disruption in any one of a large number of DNA repair factors required to remove cross-links in DNA strands, and currently there are 12 FA complementation groups152-154
. FA presents with similar neuropathology to NBS, with microcephaly as a hallmark feature. Some subgroups of FA (FANC D1 and N) result from mutations in BRCA2, or its interacting partner PALB1, and are defective in DNA DSB repair152, 155, 156
. Furthermore the D1 subgroup features brain tumors157
. Given the link between DNA repair deficiency and tumorigenesis, it is somewhat surprising that brain tumors are not more frequent in DNA repair syndromes (Text Box 2
Text Box 2: Neurodegeneration vs. Brain Tumors
Given the link between DNA damage and tumorigenesis, it might be expected that DNA repair syndromes affecting the nervous system would also present with brain tumors. While this does happen85, 86, 157
, it is more frequent in these syndromes that tumors occur in tissues outside of the brain. This probably reflects the tissue-specific consequences of gene loss. For example, xeroderma pigmentosum (XP) results from defects in different genes in the nucleotide excision repair (NER) pathway, which can lead to cancer predisposition or neurodegeneration or both. Defects that lead to neuropathology generally affect transcription-coupled repair132, 134
, while in tumor prone XP individuals, NER defects impact global genomic repair (GGR). During nervous system development DNA damage normally repaired by GGR, which could lead to tumors, may instead be eliminated by apoptosis. However, brain tumors can occur at low frequency in XP140
Syndromes resulting from DNA strand break response defects such as ataxia telangiectasia (A-T), reflect the tissue specific signaling role for ATM (ataxia telangiectasia, mutated), in which a primary function is to activate apoptosis of non-replicating DNA-damaged neural cells58
. In the immune system, where tumors mostly arise in A-T, ATM functions to maintain fidelity of immunoglobin DNA rearrangements that prevent oncogenic rearrangements53
. However, other DNA repair syndromes such as Fanconi anemia (the FANCD1 subgroup with BRCA2-BReast Cancer Associated 2-mutations) develop medulloblastoma brain tumors157
(located in the cerebellum), reflecting the occurrence of DNA damage in rapidly proliferating cells of the developing cerebellum. This is also the case for Nijmegen breakage syndrome, in which loss of NBS1 leads to microcephaly and can also result in medulloblastoma85, 86
. In these cases, medulloblastoma may occur because the DNA repair defect is quite substantial and affects the rapidly proliferating and abundant granule neuron precursors, which have a relatively high chance of acquiring mutations leading to transformation.
BLM, WS and RTS result from defective RECQ4-related helicase function158-161
. The resultant neuropathology in these syndromes is not well characterized, although the syndromes produce quite dramatic and varying phenotypes outside of the nervous system, including cancer, progeria and proportional body size defects. In the case of WS, a neurological involvement has been reported but is controversial162-164
. Why mutations in these helicases don't more substantially impact the nervous system is not clear. Their role in replication and their link to HR, suggests an important function in genomic integrity checks during neural precursor proliferation. Perhaps neurological disease is avoided in these syndromes by apoptotic elimination of damaged neural progenitors during development, or their role is not central to neural stem/progenitor replication and maintenance.
However, mutations in another helicase, the ortholog of the yeast Sen1p helicase termed Senataxin, results in ataxia with oculomotor apraxia 2 (AOA2), a syndrome characterized by pronounced cerebellar degeneration, oculomotor apraxia and sensory motor neuropathy165-170
. Additionally, different mutations in this gene can lead to a form of amyotropic lateral sclerosis171
. AOA2 is characterized by a specific defect in the response to certain types of DNA DSBs172
, but is not sensitive to ionizing radiation173
Furthermore, while distinct DNA repair pathways respond to specific DNA lesions, interplay between different DNA repair pathways is likely to provide fine-tuning of the DNA damage response. For example, pathways that deal with DNA inter-strand cross-links to prevent FA can also be involved in repair of DSBs154
, and SSB repair factors also interact with DSB repair factors174
, suggesting important interactions and cross-talk between DNA repair pathways. Unraveling the biology of DNA repair pathways and their role in disease prevention will benefit from refinements and ongoing work using mouse genetics.
Finally, the biochemical defect for many human diseases characterized by ataxia or microcephaly is unknown175
, although in some cases sensitivity towards DNA damaging agents suggest the cause is a defect in DNA repair176
. Thus, it is likely that the spectrum of DNA repair deficient diseases will continue to expand, as the respective disease-causing mutations in these syndromes are uncovered.