Asian Origin for the Worldwide-Spread Mutational Event in Machado-Joseph Disease

Abstract

Background: Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution.Objectives: To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations.Design, Setting, and Participants: We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage. Results:The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat-based haplotype. Accumulated variability suggested a postneolithic mutation, about 5774±1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families (of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93). Conclusions:The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416±434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.

Machado–Joseph disease in a Nigerian family: mutational origin and review of the literature

“…We performed the identification of MJD lineages 7,12 and genotyping of allelic variants along a 4 kb region flanking the MJD expansion 8 as previously described.…”

“…4 MJD has been found in a few African families, including those from Morocco, Algeria, Ghana, Ivory Coast, Mali, Somalia and families of African descent in the USA. [5][6][7][8][9][10] Whether independent mutational origin(s) underlie all these families remains unclear as haplotype studies are scarce. The presence of MJD worldwide is mainly explained by two ancestral lineages: the first seems to have occurred about 7000 years ago, in Asia (TTACAC, or the Joseph lineage, seen in the vast majority of non-Portuguese families, in the five continents), and another, more recent, which occurred less than 2000 years ago, responsible for MJD in some regions of Portugal (as the island of São Miguel, in the Azores and the Tagus valley) and in a few other families of proven or suspected Portuguese ancestry (GTGGCA, or the Machado lineage).…”

“…The presence of MJD worldwide is mainly explained by two ancestral lineages: the first seems to have occurred about 7000 years ago, in Asia (TTACAC, or the Joseph lineage, seen in the vast majority of non-Portuguese families, in the five continents), and another, more recent, which occurred less than 2000 years ago, responsible for MJD in some regions of Portugal (as the island of São Miguel, in the Azores and the Tagus valley) and in a few other families of proven or suspected Portuguese ancestry (GTGGCA, or the Machado lineage). 5,7,8 Calabar, capital city of the Cross River state in southeastern Nigeria, was a major slave trading port from the late 17th to the 19th century. 11 MJD has not been reported in Nigeria to the best of our knowledge.…”

Non-Mendelian Genetic Aspects in Spinocerebellar Ataxias (SCAS): The Case of Machado-Joseph Disease (MJD)

“…In the Azores, these two haplotypes were present, and were related with the islands of higher prevalence (Flores and São Miguel), indicating that two mutational events were responsible for the presence of MJD in the families of Azorean origin, a result previously disclosed by genealogical analysis (Lima et al, 1998). Aiming to determine the origin, age and dispersion of these two main mutational events, Martins et al (2007) have conducted a more extensive haplotype analysis, which revealed that the TTACAC lineage, the most frequently found in the expanded alleles of patients from all over the world, achieved its highest variability in Asia (specifically in the Japanese population). A "Short Tandem Repeat" (STR) based haplotype was identified in this population and an approximate age of 5774±1116 years was suggested.…”

Clinical evaluation of oropharyngeal dysphagia in Machado-Joseph disease

“…Japan has become one of the main center of the disease, which is also found in Brazil, India, China, Australia, Spain and France (12) .…”