Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: A genotype-phenotype study

Citations Over TimeTop 10% of 2011 papers

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.

Related Papers

• → Evaluation of Cerebellar Ataxic Patients(2022)37 cited
• → Can CANVAS due toRFC1biallelic expansions present with pure ataxia?(2023)12 cited
• → Lipid Dyshomeostasis and Inherited Cerebellar Ataxia(2022)6 cited
• → Absence of mutations in ATM , the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia(1999)16 cited
• → G.P.3.09 Cerebellar ataxia, myopathy and sensorimotor neuropathy associated with a mitochondrial m.8363G > A tRNA(Lys) gene mutation: A clinical and biochemical study(2009)