Early onset and slow progression of SCA28, a rare dominant ataxia in a large four-generation family with a novel AFG3L2 mutation

Institute for Human Genetics, University of Luebeck, Ratzeburger Allee 160, Luebeck, Germany.
European journal of human genetics: EJHG (Impact Factor: 4.23). 03/2010; 18(8):965-8. DOI: 10.1038/ejhg.2010.40
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ABSTRACT Autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders primarily affecting the cerebellum. Genetically, 26 different loci have been identified so far, although the corresponding gene has not yet been determined for 10 of them. Recently, mutations in the ATPase family gene 3-like 2 gene were presented to cause SCA type 28. To define the frequency of SCA28 mutations, we performed molecular genetic analyses in 140 unrelated familial cases with ataxia. Among other variations, we found a novel missense mutation at an evolutionarily conserved amino-acid position using a single-strand conformation polymorphism approach, followed by DNA sequencing. This amino-acid exchange p.E700K was detected in a four-generation German family and was not observed in a survey of 400 chromosomes from healthy control individuals.

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Available from: Zacharias Kohl, Aug 01, 2015
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    • "The nature of the identified mutations is suggestive that they may trigger pathogenesis by both dominant-negative and loss of function mechanisms. A p.E700K missense mutation within the AFG3L2 gene has been identified in a German family with early onset and slow progression (Edener et al., 2010). "
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    ABSTRACT: The spinocerebellar ataxias (SCAs) are a clinically, genetically and neuropathologically heterogeneous group of neurological disorders defined by variable degrees of cerebellar ataxia often accompanied by additional cerebellar and noncerebellar symptoms that, in many cases, defy differentiation based on clinical characterisation alone. The clinical symptoms are triggered by neurodegeneration of the cerebellum and its rely connections. Currently, there are 43 different genes associated with the autosomal dominant SCAs identified. Genetic studies refine the clinical diagnosis, provide molecular testing of at risk, a/presymptomatic, prenatal or preimplantation and facilitate genetic counselling in 27 SCA subtypes. Recent scientific advances are shedding light into the altered molecular pathways involved and the mechanisms by which the mutant gene products underlie neurodegeneration. This knowledge should be translated into effectively developing selective therapeutic strategies. The scope of this chapter is to provide an updated summary of the genetic aspects of the autosomal dominant SCAs. Key Concepts: Ataxia, a term that derives from the Greek, is a neurological disorder characterised by loss of control of voluntary body movements.Spinocerebellar ataxias, also known as SCAs, are a highly heterogeneous group of neurodegenerative diseases caused by cerebellar atrophy triggered by predominant loss of Purkinje cells in the cerebellum.The term ‘spinocerebellar ataxias’ is commonly used for those inherited progressive, congenital or episodic ataxias presenting an autosomal dominant inheritance.Mutations presenting incomplete penetrance in at least 43 genes are responsible for ataxia in the autosomal dominant SCAs.CAG repeat expansions encoding for polyglutamines in the gene products currently underlie neurodegeneration in seven spinocerebellar ataxia subtypes.Anticipation is a genetic phenomenon whereby the clinical symptoms become apparent at an earlier age as it is passed on to the next generation. This is associated with the germline transmission of an unstable expanded CAG-triplet repeat.Keywords:spinocerebellar ataxias;cerebellum;neurodegeneration;movement disorders;Purkinje cells;polyglutamine expansions;molecular diagnosis;genetic counselling;ataxia scales
    10/2011; John Wiley & Sons.
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    ABSTRACT: Hereditäre Ataxien stellen aufgrund der Vielfalt der möglichen genetischen Ursachen eine große diagnostische Herausforderung für die medizinische Genetik dar. Dieses Problem wird dadurch verstärkt, dass zwar die Zahl der neu identifizierten Gene in den letzten 3 Jahren durch neue Sequenziertechnologien rasant zugenommen hat, häufig jedoch nur wenige Familien weltweit Mutationen in diesen Genen aufweisen, d. h. sie extrem selten sind. Der vorliegende Artikel gibt eine Übersicht über dominante und rezessive Ataxien und berücksichtigt dabei auch die neu identifizierten Ataxie-Gene. Um den Anforderungen einer praktisch-orientierten genetischen Diagnostik gerecht zu werden, versuchen wir dabei auch, Häufigkeitseinschätzungen der betroffenen Genorte zu geben und – sofern möglich – phänotypische Eigenschaften und Biomarker zu definieren, die eine genetische Diagnostik erfolgversprechend leiten können, insbesondere bei rezessiven Ataxien. Diese diagnostischen Indikatoren werden in Form von diagnostischen Pfaden zusammengefasst, die eine Orientierung bei der mehrstufigen genetischen Diagnostik dominanter und rezessiver Ataxien geben sollen. Aufgrund der Vielzahl der Genkandidaten und des großen phänotypischen Überlappungsbereichs wird es in den meisten Fällen jedoch am zeiteffizientesten und kostengünstigsten sein, Panel-Untersuchungen mittels Next-Generation-Sequencing-Technologien durchzuführen.
    Medizinische Genetik 06/2013; 25(2). DOI:10.1007/s11825-013-0383-y · 0.09 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia type 28 is an autosomal dominant form of cerebellar ataxia (ADCA) caused by mutations in AFG3L2, a gene that encodes a subunit of the mitochondrial m-AAA protease. We screened 366 primarily Caucasian ADCA families, negative for the most common triplet expansions, for point mutations in AFG3L2 using DHPLC. Whole-gene deletions were excluded in 300 of the patients, and duplications were excluded in 129 patients. We found six missense mutations in nine unrelated index cases (9/366, 2.6%): c.1961C>T (p.Thr654Ile) in exon 15, c.1996A>G (p.Met666Val), c.1997T>G (p.Met666Arg), c.1997T>C (p.Met666Thr), c.2011G>A (p.Gly671Arg), and c.2012G>A (p.Gly671Glu) in exon 16. All mutated amino acids were located in the C-terminal proteolytic domain. In available cases, we demonstrated the mutations segregated with the disease. Mutated amino acids are highly conserved, and bioinformatic analysis indicates the substitutions are likely deleterious. This investigation demonstrates that SCA28 accounts for ∼3% of ADCA Caucasian cases negative for triplet expansions and, in extenso, to ∼1.5% of all ADCA. We further confirm both the involvement of AFG3L2 gene in SCA28 and the presence of a mutational hotspot in exons 15-16. Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs.
    Human Mutation 10/2010; 31(10):1117-24. DOI:10.1002/humu.21342 · 5.05 Impact Factor
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