Identical mutation in 55% of the ATM alleles in 11 Norwegian AT families: evidence for a founder effect

Laake, Kirsten; Telatar, Milhan; Geitvik, Gry Aarum; Hansen, Rita Øien; Heiberg, Arvid; Andresen, Anne Marie; Gatti, Richard A.; Børresen-Dale, Anne Lise

doi:10.1038/sj.ejhg.5200181

Cited by 38 publications

(38 citation statements)

References 23 publications

(39 reference statements)

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“…Previous studies have shown that specific short tandem repeat (STR) haplotypes observed in ethnic populations can be associated with founder effect mutations, i.e., ''affected haplotypes'' [Uhrhammer et al, 1995;Telatar et al, 1996;Ejima and Saaki, 1998;Laake et al, 1998;Telatar et al, 1998a,b]. Single nucleotide polymorphism (SNP) haplotyping across the region of the ATM gene is of limited informativeness [Bonnen et al, 2000;Thorstenson et al, 2001].…”

Section: Introductionmentioning

confidence: 98%

Five haplotypes account for fifty‐five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: Seven new mutations

Coutinho

Mitui

Campbell

et al. 2003

American J of Med Genetics Pt A

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We have studied the molecular genetics of 27 Brazilian families with ataxia telangiectasia (AT). Five founder effect haplotypes accounted for 55.5% of the families. AT is an autosomal recessive disorder of childhood onset characterized by progressive cerebellar ataxia, ocular apraxia, telangiectasia, immunodeficiency, radiation sensitivity, chromosomal instability, and predisposition to cancer. The ATM gene spans more than 150 kb on chromosome region 11q23.1 and encodes a product of 3056 amino acids. The ATM protein is a member of the phosphatidylinositol 3-kinase (PI-3K) family of proteins and is involved in cell cycle control and DNA repair pathways. DNA was isolated from lymphoblastoid cell lines and haplotyped using four STR markers (D11S1818, NS22, D11S2179, D11S1819) within and flanking the ATM gene; all allele sizes were standardized in advance. In addition to the STR haplotypes, SNP haplotypes were determined using 10 critical polymorphisms. The entire gene was screened sequentially by protein truncation testing (PTT), single strand conformation polymorphism (SSCP), and then denaturing high performance liquid chromatography (dHPLC) to identify the disease-causing mutations. Of the expected 54 mutations, 50 were identified. All mutations but one, led to a truncated or null form of the ATM protein (nonsense, splice site, or frameshift). Five families (18.5%) carried a deletion of 3450nt (from IVS28 to Ex31), making this one of the two most common Brazilian mutations. Mutations were located throughout the entire gene, with no clustering or hotspots. Standardized STR haplotype analysis greatly enhanced the efficiency of mutation screening.

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Section: Introductionmentioning

confidence: 98%

Five haplotypes account for fifty‐five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: Seven new mutations

Coutinho

Mitui

Campbell

et al. 2003

American J of Med Genetics Pt A

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“…The six mutations screened for are described in Table 1 (Laake et al, 1998(Laake et al, , 2000. Genotyping was performed in microtitre plates by a multiplex PCR in a 25 µl reaction volume containing 50-200 ng leukocyte DNA, 1 × Perkin Elmer buffer I, 4 mM MgCl 2 , 0.15 mM of each of the dNTPs, 0.04 U AmpliTaq, 0.2 µM of each primer, except for the primers ATEX60F and ATEX60R of which 0.6 µM was used.…”

Section: Methodsmentioning

confidence: 99%

“…The six mutations constituted 83% of the disease alleles in the Norwegian AT patients (Laake et al, 1998(Laake et al, , 2000. One single mutation constitutes 57% of the disease alleles.…”

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confidence: 99%

Screening breast cancer patients for Norwegian ATM mutations

Laake

Andersen

et al. 2000

Br J Cancer

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483 Norwegian breast cancer patients were screened for six different ataxia telangiectasia mutated ( ATM ) mutations previously found to account for 83% of the disease alleles in Norwegian ataxia telangiectasia (AT) patients. Only one carrier was found. These results provide no evidence in favour of an excess risk of breast cancer associated with heterozygosity for classical AT mutations, but remain consistent with a maximum 2.4-fold increased risk. © 2000 Cancer Research Campaign http://www.bjcancer.com

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“…At the end of the follow-up period, conjunctival biopsies were taken from the palpebral fissure and from the fornix of two of the patients (both homozygous for a Norwegian founder mutation) and were compared with biopsies from a 5-year-old Danish AT patient, compound heterozygous for two other ATM mutations. The biopsies were fixated in 4% formalin, cut into 4 lm sections and subjected to in microscope after immunohistochemical staining against Von Willebrand factor, Actin, Neuron specific enolase, Laminin, Fibronectin,Vitronectin, Vimentin, S-100 protein, Type IV collagen, glial fibrillary acid protein (GFAP) and Synaptofysin according to previously described procedures (Bek 1997 Mutation analyses of DNA prepared from peripheral blood cells were performed using several techniques including protein truncating test, denaturing gradient gel electrophoresis, heteroduplex analysis and denaturing high-performance liquid chromatography followed by sequencing, as previously described (Laake et al 1998). The ATM mutation status for seven of the patients has been reported previously (Laake et al 2000).…”

Section: Methodsmentioning

confidence: 99%

“…Because five patients were homozygous for the Norwegian founder mutation c.3245delATCinsTGAT (Laake et al 1998), we also looked for a possible phenotype ⁄ genotype relationship.…”

Section: Introductionmentioning

confidence: 99%

Ocular findings in Norwegian patients with ataxia‐telangiectasia: a 5 year prospective cohort study

Riise¹,

Ygge²,

Lindman³

et al. 2007

Acta Ophthalmologica Scandinavica

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ABSTRACT.Purpose: To describe the outcome of ophthalmologic examination of 10 Norwegian children with ataxia-telangiectasia (AT) followed through 5 years. Methods: Ten Norwegian patients with AT aged 2-22 years (three females, seven males) were examined. The diagnosis was confirmed clinically as well as with molecular genetic studies. Conventional ophthalmologic examination was performed and supplemented by photographs of the conjunctiva, video recordings and registration of eye motility in five consecutive years. Additionally conjunctival biopsies were performed at the end of the follow-up period. Results: General ataxia was usually detected when the child started to walk. All children over the age of 4 years had abnormal saccade movements, a form of ocular motor apraxia. Conjunctival telangiectasias were mostly visible at 4-5 years, primarily within the palpebral fissure. Immunohistochemical examination of conjunctival biopsies showed an increased number of cross-sections of blood vessels and neurons surrounded by glial tissue. There was a tendency to slightly earlier onset of conjunctival telangiectasias in the patients homozygous for a founder mutation compared with the other patients. Conclusion: The diagnosis of AT can be supported at preschool age by the onset of ocular motor apraxia and conjunctival telangiectasias. The findings become more prominent with age. The conjunctival telangiectasias seem to appear slightly earlier in the patients who are homozygous for a Norwegian founder mutation than in the rest of the patients.

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Identical mutation in 55% of the ATM alleles in 11 Norwegian AT families: evidence for a founder effect

Cited by 38 publications

References 23 publications

Five haplotypes account for fifty‐five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: Seven new mutations

Five haplotypes account for fifty‐five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: Seven new mutations

Screening breast cancer patients for Norwegian ATM mutations

Ocular findings in Norwegian patients with ataxia‐telangiectasia: a 5 year prospective cohort study

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