Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Class switch recombination (CSR) is a region-specific, transcriptionally regulated, nonhomologous recombinational process that is initiated by activation-induced cytidine deaminase (AID). The initial lesions in the switch (S) regions are processed and resolved, leading to a recombination of the two S regions involved. The mechanism involved in the repair and ligation of the broken DNA ends is however still unclear. Here, we describe that switching is less efficient in cells from patients with Mre11 deficiency (Ataxia-Telangiectasia-like disorder, ATLD) and, more importantly, that the switch recombination junctions resulting from the in vivo switching events are aberrant. There was a trend toward an increased usage of microhomology (> or =4 bp) at the switch junctions in both ATLD and Nijmegen breakage syndrome (NBS) patients. However, the DNA ends were not joined as "perfectly" as those from Ataxia-Telangiectasia (A-T) patients and 1-2 bp mutations or insertions were often observed. In switch junctions from ATLD patients, there were fewer base substitutions due to transitions and, most strikingly, the substitutions that occurred most often in controls, C --> T transitions, never occurred at, or close to, the junctions derived from the ATLD patients. In switch junctions from NBS patients, all base substitutions were observed at the G/C nucleotides, and transitions were preferred. These data suggest that the Mre11-Rad50-Nbs1 complex (Mre11 complex) is involved in the nonhomologous end joining pathway in CSR and that Mre11, Nbs1, and protein mutated in ataxia-telangiectasia (ATM) might have both common and independent roles in this process.
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PMID:Delineation of the role of the Mre11 complex in class switch recombination. 1474 72

Mre11/Rad50/Nbs1 complex (MRN) is essential to suppress the generation of double-strand breaks (DSBs) during DNA replication. MRN also plays a role in the response to DSBs created by DNA damage. Hypomorphic mutations in Mre11 (which causes an ataxia-telangiectasia-like disease [ATLD]) and mutations in the ataxia-telangiectasia-mutated (ATM) gene lead to defects in handling damaged DNA and to similar clinical and cellular phenotypes. Using Xenopus egg extracts, we have designed a simple assay to define the biochemistry of Mre11. MRN is required for efficient activation of the DNA damage response induced by DSBs. We isolated a high molecular weight DNA damage signaling complex that includes MRN, damaged DNA molecules, and activated ATM. Complex formation is partially dependent upon Zn(2+) and requires an intact Mre11 C-terminal domain that is deleted in some ATLD patients. The ATLD truncation can still perform the role of Mre11 during replication. Our work demonstrates the role of Mre11 in assembling DNA damage signaling centers that are reminiscent of irradiation-induced foci. It also provides a molecular explanation for the similarities between ataxia-telangiectasia (A-T) and ATLD.
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PMID:Mre11 assembles linear DNA fragments into DNA damage signaling complexes. 1513 96

Progressive myoclonic ataxia (PMA) is a clinical syndrome defined as progressive ataxia and myoclonus and infrequent seizures in the absence of progressive dementia. Due to the extremely heterogeneous nature of PMA, a large proportion of PMA cases remain molecularly undiagnosed. The aim of this study was to clarify the molecular etiology of PMA. The patient was a 52-year-old female from consanguineous parents. She developed a jerking neck movement at age 9, which gradually expanded to her entire body. On physical examination at age 47, she exhibited generalized, spontaneous myoclonus that occurred continuously. She also presented with mild limb and truncal ataxia. An electroencephalogram revealed no abnormalities. A brain MRI displayed no atrophy of the cerebellum. Electrophysiological studies suggested myoclonus of a subcortical origin. For further evaluation, we performed exome sequencing, and we identified a novel homozygous missense mutation in the MRE11 gene (NM_005590:c.140C>T:p.A47V). Subsequently, we analyzed the expression of MRE11 and related proteins (RAD50 and NBS1) via Western blot, and they were markedly decreased compared to a healthy control. Mutations in the MRE11 gene have been known to cause an ataxia-telangiectasia-like (ATLD) disorder. Accumulating evidence has indicated that its wide phenotypic variations in ATLD correspond to genotypic differences. Interestingly, our case exhibited a relatively mild decrease in NBS1 compared to previously reported cases of a homozygous missense mutation, which may account for the milder phenotype in this patient. Moreover, together with a recently reported case of an MRE11 mutation, it is suggested that MRE11 mutations can present as PMA.
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PMID:Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia. 2433 46