The hallmark of A-T is progressive neurodegeneration, manifested as cerebellar ataxia (Boder et al.
1958; Barlow et al.
1996). A-T occurs in early childhood, with an incidence varying from 1 in 40,000 to 100,000 births in various ethnic areas (Swift et al.
1986), and caused by biallelic mutations of
Atm gene located on chromosome 11q23.1 (Gatti et al.
1988).
Atm gene, identified in 1995 (Savitsky et al.
1995), is very large and is comprised of 66 exons with an open reading frame of 9,168 nucleotides.
Atm gene product, ATM, is a protein kinase with 3,050 amino acids and belongs to the phosphoinositide 3-kinase-related protein kinase super family. ATM is mainly located in the nucleus, although it has been found in cytosol associated with peroxisomes (Watters et al.
1999). As a multifunctional protein kinase, ATM, upon its autophosphorylation, plays a critical role in regulation of cell cycle control, DNA damage and repair, and cell survival and death by orchestrating the phosphorylation of multiple substrates (Goodarzi et al.
2004; Kozlov et al.
2011). As a caretaker, ATM, which also is a redox thiol-sensitive protein kinase, functions by activating multiple redox-sensitive or phosphorylation-sensitive mechanisms responsible for maintaining genomic, telomeric, and chromosomal integrity under conditions of genomic or redox stress primarily during postnatal development (Barlow et al.
1999; Yan et al.
2001; Yan et al.
2006). Recently, a large-scale proteomic analysis of protein phosphorylation in response to DNA damage revealed that more than 700 proteins and 900 phosphorylation sites were correlated with ATM and ATR (ataxia telangiectasia and Rad3-related) (Matsuoka et al.
2007).
To date, more than 500
Atm mutations have been identified as the disease-causing mutations (
http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ATM). The mutations can be found in every exon with no apparent hotspots. The majority of
Atm mutations are frameshift or nonsense mutations (Wright et al.
1996; Concannon and Gatti
1997), which are predicted to truncate the whole ATM protein. Other
Atm mutations include missense mutation, splicing, and large genomic deletion/duplication, etc.
In China, less than 30 A-T patients have been reported by different hospitals, and only two unique
Atm mutations have been identified so far (Jiang et al.
2006). This calls a question whether the incidence of A-T in Chinese population is lower than that in other countries or the A-T cases are technically misdiagnosed there. Therefore, it is urgent to study Chinese A-T, including
Atm mutation analysis. In the present study, we screened 12 novel
Atm mutations in 8 Chinese A-T patients from 6 unrelated families. Our results showed an inkling that
Atm mutations in Chinese A-T patients are diverse, which, in turn, make it possible to better identify individual A-T patients who are suitable for future customized mutation-targeted therapies based on their
Atm mutated status.