Abstract
Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is considered the most common form of SCA worldwide. The main goal of this study was to investigate the presence of segregation ratio distortion (SRD) during transmissions of ATXN3 alleles by MJD patients, evaluating the putative role of SRD in the epidemiological representation of the disease. Sixty-two complete sibships, each with one clinically affected parent, totalling 330 transmissions were selected according to defined criteria and used for segregation analysis. Onset data from MJD patients with Azorean origin was used for residual risk estimates according to different ages. Residual risk values were applied to unaffected offspring to calculate the probability of inheriting the expanded allele. The proportion of offspring that received the expanded or the normal allele from the affected parent was calculated to determine the presence of SRD during transmissions of ATXN3 alleles by MJD patients. Segregation of ATXN3 alleles was in accordance with the expected Mendelian proportions (χ 2 = 0.982, P = 0.322). However, there was a tendency favouring the transmission of the normal alleles. Thus, SRD is not a potential mechanism on the basis of MJD epidemiological representation.
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References
Abade A, Santos C, Lima M, Freire-Gonçalves A, Carvalho S, Coutinho P (2000) Reproductive success in families with Machado–Joseph disease from the center of Portugal. In: Varela TA (ed) Investigaciones en Biodiversidad Humana. Universidade de Santiago de Compostela, Santiago de Compostela
Bettencourt C, Santos C, Kay T, Silva C, Vasconcelos J, Santos J, Maciel P, Lima M (2005) Clinical presentation and size of the CAG tract in Machado–Joseph disease patients from the Azores Islands (Portugal). Açoreana 10(2):311–318
Bettencourt C, Fialho RN, Santos C, Montiel R, Bruges-Armas J, Maciel P, Lima M (2008) Segregation distortion of wild-type alleles at the Machado–Joseph disease locus: a study in normal families from the Azores islands (Portugal). J Hum Genet 53(4):333–339
Cagnoli C, Mariotti C, Taroni F, Seri M, Brussino A, Michielotto C, Grisoli M, Di Bella D, Migone N, Gellera C, Di Donato S, Brusco A (2006) SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22–q11.2. Brain 129:235–242
Coutinho P (1992) Doença de Machado–Joseph: Tentativa de Definição, PhD Dissertation, Instituto de Ciências Biomédicas Abel Salazar, Porto
Coutinho P, Andrade C (1978) Autosomal dominant system degeneration in Portuguese families of the Azores Islands. Neurology 28:703–709
Drüsedau M, Dreesen JC, De Die-Smulders C, Hardy K, Bras M, Dumoulin JC, Evers JL, Smeets HJ, Geraedts JP, Herbergs J (2004) Preimplantation genetic diagnosis of spinocerebellar ataxia 3 by (CAG)(n) repeat detection. Mol Hum Reprod 10:71–75
Grewal RP, Cancel G, Leeflang EP, Dürr A, McPeek MS, Draghinas D, Yao X, Stevanin G, Alnot MO, Brice A, Arnheim N (1999) French Machado–Joseph disease patients do not exhibit gametic segregation distortion: a sperm typing analysis. Hum Mol Genet 8:1779–1784
Ichikawa Y, Goto J, Hattori M, Toyoda A, Ishii K, Jeong SY, Hashida H, Masuda N, Ogata K, Kasai F, Hirai M, Maciel P, Rouleau GA, Sakaki Y, Kanazawa I (2001) The genomic structure and expression of MJD, the Machado–Joseph disease gene. J Hum Genet 46:413–422
Ikeuchi T, Igarashi S, Takiyama Y, Onodera O, Oyake M, Takano H, Koide R, Tanaka H, Tsuji S (1996) Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado–Joseph disease: the mutant allele is preferentially transmitted in male meiosis. Am J Hum Genet 58:730–733
Iughetti P, Otto PA, Zatz M, Passos Bueno MR, Marie SK (1998) Different behavior in the paternally vs. maternally inherited mutated allele in Brazilian Machado–Joseph (MJD1) families. Am J Med Genet 77:246–248
Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, Kimura J, Narumiya S, Kakizuka A (1994) CAG expansions in a novel gene for Machado–Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228
Lima M (1996) Machado–Joseph disease in the Azores: an epidemiological, genealogical and genetic study. PhD dissertation (in Portuguese). University of the Azores, Ponta Delgada
Lima M, Mayer FM, Coutinho P, Abade A (1998) Origins of a mutation: population genetics of Machado–Joseph disease in the Azores (Portugal). Hum Biol 70:1011–1023
Lima M, Smith MT, Silva C, Abade A, Mayer FM, Coutinho P (2001) Natural selection at the MJD locus: phenotypic diversity, survival and fertility among Machado–Joseph disease patients from the Azores. J Biosoc Sci 33:361–373
Maciel P, Costa MC, Ferro A, Rousseau M, Santos CS, Gaspar C, Barros J, Rouleau GA, Coutinho P, Sequeiros J (2001) Improvement in the molecular diagnosis of Machado–Joseph disease. Arch Neurol 58:1821–1827
Nakano KK, Dawson DM, Spence A (1972) Machado disease. A hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology 22:49–55
Riess O, Epplen JT, Amoiridis G, Przuntek H, Schols L (1997) Transmission distortion of the mutant alleles in spinocerebellar ataxia. Hum Genet 99:282–284
Santos C, Abade A, Lima M, Freire-Gonçalves A, Carvalho S, Coutinho P (2000) Machado–Joseph disease in Portugal: the beginning of a long ‘puzzle’. In: Varela TA (ed) Investigaciones en Biodiversidad Humana. Universidade de Santiago de Compostela, Santiago de Compostela
Sequeiros J (1993) Machado–Joseph disease: epidemiology, genetics and genetic epidemiology. In: Lechtenberg R (ed) Handbook of cerebellar diseases. Marcel Dekker, New York
Sequeiros J (1996) General protocol of the national program of predictive testing and genetic counselling in Machado–Joseph disease. In: Sequeiros J (ed) Predictive testing in Machado–Joseph disease (in Portuguese). UnIGENe-IBMC, Porto
Sequeiros J, Maciel P, Taborda F, Lêdo S, Rocha JC, Lopes A, Reto F, Fortuna AM, Rousseau M, Fleming M, Coutinho P, Rouleau GA, Jorge CS (1998) Prenatal diagnosis of Machado–Joseph disease by direct mutation analysis. Prena Diagn 18:611–617
SPSS Inc. (2006) SPSS for Windows, Release 15.0. SPSS Inc., Chicago
Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, Shimazaki H, Soutome M, Endo K, Ohta S, Kagawa Y, Kanazawa I, Mizuno Y, Yoshida M, Yuasa T, Horikawa Y, Oyanagi K, Nagai H, Kondo T, Inuzuka T, Onodera O, Tsuji S (1993) The gene for Machado–Joseph disease maps to human chromosome 14q. Nat Genet 4:300–304
Takiyama Y, Sakoe K, Soutome M, Namekawa M, Ogawa T, Nakano I, Igarashi S, Oyake M, Tanaka H, Tsuji S, Nishizawa M (1997) Single sperm analysis of the CAG repeats in the gene for Machado–Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability. Hum Mol Genet 6(7):1063–1068
Woods BT, Schaumburg HH (1972) Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia. A unique and partially treatable clinico-pathological entity. J Neurol Sci 17:149–166
Young ID (2007) Introduction to risk calculation in genetic counselling, 3rd edn. Oxford University Press, New York
Acknowledgments
This work was supported by “Projecto Regional Integrado—DMJ (PRI-DMJ)” (funded by Regional Government of the Azores). CB (SFRH/BD/21875/2005) is a recipient of a Ph.D. grant, and CS (SFRH/BPD/20944/2004) is a postdoctoral fellow from “Fundação para a Ciência e a Tecnologia” (FCT).
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Bettencourt, C., Santos, C., Kay, T. et al. Analysis of segregation patterns in Machado–Joseph disease pedigrees. J Hum Genet 53, 920–923 (2008). https://doi.org/10.1007/s10038-008-0330-y
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DOI: https://doi.org/10.1007/s10038-008-0330-y
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