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Genetisches Modell der autosomal-rezessiv erblichen proximalen spinalen Muskelatrophie

Genetic model of autosomal recessive proximal spinal muscular atrophy

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medizinische genetik

Zusammenfassung

Die proximale infantile und juvenile spinale Muskelatrophie (SMA) ist eine der häufigsten autosomal-rezessive Erbkrankheiten. Man unterteilt die Patienten in 3 Gruppen, SMA Typ I-III, abhängig von der Schwere der Erkrankung (den erreichten Meilensteinen). Das hauptsächlich verantwortliche Gen, das Survival-motor-neuron(SMN1)-Gen, ist auf Chromosom 5 lokalisiert. Während das Normalallel meist mit einer oder 2 SMN1-Kopien vorliegt, sind die Defektallele bei den meisten Patienten von einer Deletion betroffen; bei einigen liegen Punktmutationen vor. Bei den Deletionen wiederum unterscheidet man zwischen einfacher und großer Deletion, die über das SMN1-Gen hinausgeht. Ein homozygotes Auftreten letzterer führt zu pränataler Letalität.

Für die vorliegende Arbeit wurden zahlreiche in der Literatur verfügbare Daten zur SMA Typ I-III zusammengetragen und in ihrer Abhängigkeit in einem genetischen Modell zusammengefasst. So war es möglich, fehlende Parameter zu schätzen, um genauere Aussagen über Genotypen machen zu können. Die einzelnen Allelfrequenzen konnten wie folgt geschätzt werden:

Normalallel b (1 SMN1-Kopie): ≈ 0,9527; Normalallel c (2 SMN1-Kopien): ≈ 0,0362; einfache Deletion a (0 SMN1-Kopien): ≈ 0,0104; Punktmutation d (1 SMN1-Kopie): ≈ 0,0003; große Deletion g (0 SMN1-Kopien): ≈ 0,0004. Die Genhäufigkeit beträgt etwa 1:90 mit einer Heterozygtenfrequenz von 1:46.

Abstract

Proximal spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases. According to the achieved milestones, SMA is divided into 3 groups: SMA types I–III. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene, which is located on chromosome 5. Wild type alleles usually have one or two SMN1 gene copies, disease alleles may show deletions, large scale deletions, or point mutations.

The proposed genetic model is based on published data on SMA types I–III. The complex genetic model of SMA allows all parameters—even those which have not been assessed so far—to be calculated. The SMN1 allele frequencies included the following: normal allele b (1 copy of SMN1): ≈ 0.9527; normal allele c (2 copies of SMN1): ≈ 0.0362; deletion a (0 copies of SMN1): ≈ 0.0104; point mutation d (1 copy of SMN1): ≈ 0.0003; large scale deletion g (0 copies of SMN1): ≈ 0.0004. The result is a gene frequency of approximately 1:90 and a carrier frequency of about 1:46.

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Einhaltung ethischer Richtlinien

Interessenkonflikt. S. Langer, S. Rudnik-Schöneborn, K. Zerres und T. Grimm geben an, dass kein Interessenkonflikt besteht. Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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  1. Abteilung für Medizinische Genetik im Institut für Humangenetik, Universität Würzburg, Biozentrum, Am Hubland, 97074, Würzburg, Deutschland

    S. Langer &  T. Grimm

  2. Institut für Humangenetik, RWTH, Aachen, Aachen, Deutschland

    S. Rudnik-Schöneborn & K. Zerres

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  1. S. Langer
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  2. S. Rudnik-Schöneborn
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Correspondence to T. Grimm.

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Langer, S., Rudnik-Schöneborn, S., Zerres, K. et al. Genetisches Modell der autosomal-rezessiv erblichen proximalen spinalen Muskelatrophie. medgen 25, 337–346 (2013). https://doi.org/10.1007/s11825-013-0402-z

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