Chromosome instability and X‐ray hypersensitivity in a microcephalic and growth‐retarded child

Abstract

We report on a microcephalic, growth-retarded newborn girl without major anomalies who has chromosome instability in lymphocytes and fibroblasts. Frequent involvement of bands 7p13, 7q34, 14q11, and 14q32 suggested the diagnosis of ataxia telangiectasia (AT) or a related disorder. Supportive evidence was radioresistant DNA synthesis in fibroblasts and radiation hypersensitivity of short-term lymphocyte cultures. Follow-up for nearly 4 years showed largely normal development, and no signs of telangiectasia, ataxia, or immunodeficiency. Serum AFP levels turned from elevated at age 5 months to normal at age 2 years. We propose that our patient belongs to the expanding category of "AT-related" genetic disorders, probably to the Nijmegen breakage syndrome.

ATM Protein-dependent Phosphorylation of Rad50 Protein Regulates DNA Repair and Cell Cycle Control

“…This is referred to as radioresistant DNA synthesis and is used as a measure of the S-phase checkpoint. This phenomenon has been reported previously in cells from the Rad50-deficient patient (8,12). Radioresistant DNA synthesis is normally determined by incorporation of radioactive nucleotide into DNA and is subject to considerable variability.…”

“…Although several families with ATLD and NBS have been identified, only a single patient with Rad50 deficiency has been described (8). This patient was initially diagnosed as probably having NBS because of overlap in features such as microcephaly, mental retardation, bird-like face, and short stature (12). However, more recently this patient was found to be compound heterozygous for mutations (3277C3 T (R1093X) and 3939A3 T (X1313Y) extX*66) in the RAD50 gene that gave rise to low levels of unstable Rad50 protein (8).…”

DNA strand break repair and neurodegeneration

“…A number of hypomorphic mutations in NBS1, MRE11 and RAD50 have been identified in patients with Nijmegen breakage syndrome (NBS), A-T-like disorder (A-TLD) and NBS-like disorder (NBSLD) respectively. Patients with these mutations show a phenotypic spectrum similar to other NHEJ disorders (microcephaly, immunodeficiency, radiosensitivity and cancer predisposition) with varying severity that may reflect the nature of the hypomorphic mutation on protein levels and DSB repair activity, or functional differences between these proteins [67][68][69][70][71][72].…”

Radiation‐induced DNA damage and repair in peripheral blood mononuclear cells from Nijmegen breakage syndrome patients and carriers assessed by the Comet assay

“…Another possible explanation for the difficulty in detecting an increase in initial DNA damage for the NBS patients and heterozygotes is the great variability among NBS, which has been reported when radioresistant DNA synthesis or the presence of a G2-block is evaluated (see Introduction [Barbi et al, 1991;Chrzanowska et al, 1995;Tupler et al, 1997]). An increased resistance to g-irradiation-induced DNA synthesis was found in only 8 out of 11 NBS cases [Chrzanowska et al, 1995].…”

“…The resistance of NBS cells to radiation, however, has been reported to vary from increased [Taalman et al, 1983;Sullivan et al, 1997;Carney et al, 1998] through moderate [Young and Painter, 1989;Tupler et al, 1997] to nearly normal [Girard et al, 2000;Antoccia et al, 2002;Little et al, 2002]. Some authors indicate that these observations can be explained by the heterogeneity of NBS patients [Barbi et al, 1991;Chrzanowska et al, 1995;Tupler et al, 1997].…”