Age and origin of the FCMD 3′-untranslated-region retrotransposal insertion mutation causing Fukuyama-type congenital muscular dystrophy in the Japanese population

Department of Psychology, Catholic University of the Sacred Heart, Milan, Italy.
Human Genetics (Impact Factor: 4.82). 01/2001; 107(6):559-67. DOI: 10.1007/s004390000421
Source: PubMed


Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive disorder with a high prevalence in the Japanese population, is characterised by severe muscular dystrophy associated with brain malformation (cortical dysgenesis) and mental retardation. In Japan, 87% of FCMD-bearing chromosomes carry a 3-kb retrotransposal insertion of tandemly repeated sequences within the disease gene recently identified on chromosome 9q31, and most of them share a common founder haplotype. FCMD is the first human disease known to be caused primarily by an ancient retrotransposal integration. By applying two methods for the study of linkage disequilibrium between flanking polymorphic markers and the disease locus, and of its decay over time, the age of the insertion mutation causing FCMD in Japanese patients is calculated to be approximately 102 generations (95% confidence interval: 86-117 g), or slightly less. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes back to the time (or a few centuries before) the Yayoi people started migrating to Japan from the Korean peninsula. This finding makes the molecular population genetics of FCMD understandable in the context of Japan's history and the founder effect consistent with the prevalent theory on the origins of the modern Japanese population.

4 Reads
  • Source
    • "Allele frequencies in unrelated normal chromosomes were found by genotyping 62 unrelated individuals of the general population. Estimation of the age of the mutation was based on the following formula: generations ¼ log d=log (1 À y) (Risch et al., 1995; see also Colombo et al., 2000, and Chan et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the COL4A3/COL4A4 genes of type IV collagen account for about 40% of cases of thin basement membrane nephropathy, a condition that is estimated to affect 1% or more of the general population. We recently described 10 Cypriot families with familial hematuria and thin basement membrane nephropathy in the presence of focal segmental glomerulosclerosis, with founder mutations on COL4A3 gene. Seven of the families carried mutation G1334E on haplotype K, and another three carried mutation G871C on haplotype Ky. In this report we performed extension of the haplotypes with additional polymorphic markers, 12 for haplotype K and 22 for haplotype Ky, to estimate the linkage disequilibrium value between the mutation and flanking noncommon markers. Haplotype Ky extended to 13.71 Mb, but we did not attempt further analysis owing to the small number of chromosomes. Haplotype K extended to 3.83 Mb, thereby suggesting that it was a much older event compared to mutation G871C. Mutation G1334E was calculated to be about 5-10 generations old with a possible origin between 1693 and 1818 AD, during the Ottoman ruling of the island. Both mutations are clustered in specific geographic regions with apparently formerly isolated populations, although mutation G1334E has been detected elsewhere on the island. The identification of founder mutations in large families with microscopic hematuria greatly facilitates presymptomatic diagnosis and provides useful information on the history of the population, while it may also assist in association studies in search for disease modifier genes.
    Genetic Testing 07/2008; 12(2):273-8. DOI:10.1089/gte.2007.0110 · 1.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transposons are mobile genetic elements that live parasitically within the genome of cellular organisms. They can affect the fitness of their hosts by influencing gene function, gene activity, genome structure, and overall DNA content. Since excessive transposon activity can result in a high mutagenic rate and genomic instability, eukaryotes have evolved epigenetic mechanisms to reduce transposition to manageable levels. The alga Chlamydomonas reinhardtii appears to have several, at least partly independent, transposon repression pathways that operate at either the transcriptional or the post-transcriptional level. Two genes have been implicated in the transcriptional silencing of transposons and single-copy transgenes: Mut9, which encodes a novel serine/threonine protein kinase capable of phosphorylating histones H3 and H2A, and Mut11, which encodes a WD40-repeat containing protein. The Mut11 protein functions as a subunit of a histone methyltransferase complex(es) that is required for monomethylation of histone H3 lysine 4 and the maintenance of repressed euchromatic domains. These mechanisms of transcriptional gene silencing operate independently from the RNA interference (RNAi) machinery. In contrast, a putative DEAH-box RNA helicase (Mut6) has been demonstrated to participate in the post-transcriptional suppression of transgenes and transposons. The Mut6 helicase is homologous to an essential Saccharomyces cerevisiae precursor messenger RNA (pre-mRNA) splicing factor and appears to be required for the processing of specific Chlamydomonas pre-mRNAs, including those corresponding to components of the RNAi machinery such as Dicer and Ago1. These findings implicate RNAi in the post-transcriptional repression of transposons in Chlamydomonas. Thus, multiple silencing mechanisms appear to operate as a defense system against the expansion of transposable elements in algae. These independent repression pathways likely increase the genetic robustness of transposon silencing against mutational and environmental perturbations.
    01/1970: pages 159-178;
  • [Show abstract] [Hide abstract]
    ABSTRACT: A two-dimensional computer model of an oxygen sensor-based micro immunosensor was developed based on the finite element method. The results showed the feasibility of the model immunosensor. The working range of the model sensor was about 3 decades, which agrees well with the experimental data reported in the literature. Significantly different performance was also found between a sensor in a stop-flow setup and a sensor in a flow cell
    Engineering in Medicine and Biology Society, 1994. Engineering Advances: New Opportunities for Biomedical Engineers. Proceedings of the 16th Annual International Conference of the IEEE; 02/1994
Show more