Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7.
Heather Trang,Sabrina Y. Stanley,Paul S. Thorner,Hannaneh Faghfoury,Andreas Schulze,Cynthia Hawkins,Christopher E. Pearson,Grace Yoon +7 more
Reads0
Chats0
TLDR
The first case to date of maternally transmitted infantile spinocerebellar ataxia type 7 (SCA7), in which a tract of CAG45 expands to lengths as large as (CAG)92-250 is reported, which has implications for diagnosis and counseling among families of patients with SCA7.Abstract:
Importance We report the first case to date of maternally transmitted infantile spinocerebellar ataxia type 7 (SCA7), in which a tract of (CAG)45 expands to lengths as large as (CAG)92-250. Observations A 38-year-old woman with classic SCA7 (and a son, who died at age 3 years) had pronounced cerebellar atrophy and a renal biopsy specimen that showed focal segmental glomerulosclerosis with abnormal podocytes containing cytoplasmic inclusions. Polymerase chain reaction amplification across the SCA7 repeat tract assessed expansion levels in tissues of the affected son. High levels of somatic CAG instability were observed in blood, kidney, and skeletal muscle. This transmitted expansion is considerably larger than previously reported maternal transmission expansions of 5 to 10 gained repeats. Conclusions and Relevance We document the first intertissue CAG instability reported to date in patients with SCA7, similar to SCA7 mouse models. Infantile SCA7, which is often paternally transmitted, can rarely arise by maternal transmission, which has implications for diagnosis and counseling among families of patients with SCA7.read more
Citations
More filters
Book ChapterDOI
Repeat expansion diseases.
TL;DR: More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome as mentioned in this paper, including tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions.
Journal ArticleDOI
DNA repair in the trinucleotide repeat disorders.
TL;DR: Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.
Journal ArticleDOI
The Repeat Expansion Diseases: The dark side of DNA repair
Xiao-Nan Zhao,Karen Usdin +1 more
TL;DR: This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion.
Journal ArticleDOI
TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease.
Michael P. Fautsch,Eric D. Wieben,Keith H. Baratz,Nihar Bhattacharyya,Amanda N. Sadan,Nathaniel J. Hafford-Tear,Stephen J Tuft,Stephen J Tuft,Alice E. Davidson +8 more
TL;DR: Research implicating the repeat expansion in disease pathogenesis is summarised, the phenotype-genotype correlations between FECD and CTG18.1 expansion are defined, and a forward-thinking perspective on key unanswered questions that remain in the field is provided.
Journal ArticleDOI
Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7
TL;DR: A better understanding of the principal molecular mechanisms by which mutant ATXN7 elicits neurotoxicity, and how interconnected pathogenic cascades lead to neurodegeneration is needed for the development of effective therapies is needed.
References
More filters
Journal ArticleDOI
Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I
TL;DR: In this paper, a sequence analysis of the repeat from 126 chromosomes reveals an interrupted repeat configuration in 98% of the unexpanded alleles but a contiguous repeat (CAG)n configuration in 30 expanded alleles from seven SCA1 families.
Journal ArticleDOI
Repeat instability as the basis for human diseases and as a potential target for therapy
Arturo López Castel,John D. Cleary,John D. Cleary,Christopher E. Pearson,Christopher E. Pearson +4 more
TL;DR: How repeat instability is mediated by DNA replication, repair, recombination, transcription and epigenetics may explain its contribution to pathogenesis and give insights into therapeutic strategies to block expansions or induce contractions.
Journal ArticleDOI
Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy
Catherine Tsilfidis,Alex MacKenzie,Alex MacKenzie,Gabrielle Mettler,Juana Barceló,Robert G. Korneluk,Robert G. Korneluk +6 more
TL;DR: Infants with severe congenital DM, as well as their mothers, are shown to have on average a greater amplification of the CTG repeat than is seen in the noncongenital DM population, providing evidence for the existence of genetic anticipation in the transmission of DM.
Journal ArticleDOI
Molecular and Clinical Correlations in Autosomal Dominant Cerebellar Ataxia with Progressive Macular Dystrophy (SCA7)
Gilles David,Alexandra Durr,Giovanni Stevanin,Géraldine Cancel,Nacer Abbas,Ali Benomar,Samir Belal,Anne-Sophie Lebre,Myriem Abada-Bendib,D. Grid,Monica Holmberg,Mohamed Yahyaoui,Fayçal Hentati,T. Chkili,Yves Agid,Alexis Brice +15 more
TL;DR: The mutation was highly unstable during transmission, with a mean increase of 10 +/- 16 CAG repeats, which was significantly greater in paternal than in maternal transmissions, and correlated well with the marked anticipation observed in the families.
Journal ArticleDOI
Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype
TL;DR: Data show a wide spectrum of phenotypic abnormalities in SCA-7 and define an infantile phenotype caused by the largest CAG repeat expansion described to date.
Related Papers (5)
Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease
Jong-Min Lee,Vanessa C. Wheeler,Michael J. Chao,Jean Paul G. Vonsattel,Ricardo Mouro Pinto,Diane Lucente,Kawther Abu-Elneel,Eliana Marisa Ramos,Jayalakshmi S. Mysore,Tammy Gillis,Marcy E. MacDonald,James F. Gusella,Denise Harold,Timothy Stone,Valentina Escott-Price,Jun Han,Alexey Vedernikov,Peter Holmans,Lesley Jones,Seung Kwak,Mithra Mahmoudi,Michael Orth,G. Bernhard Landwehrmeyer,Jane S. Paulsen,E. Ray Dorsey,Ira Shoulson,Richard H. Myers +26 more
Disease-associated repeat instability and mismatch repair
Spinocerebellar Ataxia Type 10: A Disease Caused by a Large ATTCT Repeat Expansion
Tohru Matsuura,Tetsuo Ashizawa +1 more