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Neuromuscul Disord. 2019 Mar;29(3):187-191. doi: 10.1016/j.nmd.2018.12.003. Epub 2018 Dec 15.

Reevaluating the pathogenicity of the mutation c.1194 +5 G>A in GAA gene by functional analysis of RNA in a 61-year-old woman diagnosed with Pompe disease by muscle biopsy.

Author information

1
Unidad de Oncogenética Molecular, Instituto de Genética Médica y Molecular (INGEMM), Edificio Quirúrgico Planta-2, Hospital Universitario La Paz, 28046 Madrid, Spain.
2
Unidad de Oncogenética Molecular, Instituto de Genética Médica y Molecular (INGEMM), Edificio Quirúrgico Planta-2, Hospital Universitario La Paz, 28046 Madrid, Spain; Institute of Cardiovascular Science, Faculty of Population Health, University College London, London WC1E 6BT, UK.
3
Neurology Department, University General Hospital of Guadalajara, Spain.
4
Unidad de Oncogenética Molecular, Instituto de Genética Médica y Molecular (INGEMM), Edificio Quirúrgico Planta-2, Hospital Universitario La Paz, 28046 Madrid, Spain; Department of Biochemistry, Faculty of Medicine, Autonoma University of Madrid, 28046 Madrid, Spain. Electronic address: jesus.solera@uam.es.

Abstract

Glycogen storage disease type II, or Pompe disease, is an autosomal recessive disorder caused by deficiency of lysosomal acid alpha-glucosidase (GAA). We performed genetic analysis to confirm the diagnosis of Pompe disease in a 61-year-old patient with progressive weakness in extremities, severe Sleep Apnea-Hypopnea Syndrome, a significant reduction of alpha-glucosidase in liquid sample of peripheral blood and muscular biopsy diagnosis. GAA gene sequencing showed the patient is homozygous for the splice-site mutation c.1194+5G>A, considered as nonpathogenic in Pompe Center mutation database. Further molecular RNA characterization of GAA transcripts allowed us to identify abnormal processing of pre-mRNA, leading to aberrant transcripts and a significant reduction of GAA mRNA levels. Our results indicate that c.1194+5G>A is a pathogenic splice-site mutation and should be considered as such for diagnostic purposes. This study emphasizes the potential role of functional studies to determine the consequences of mutations with no evident pathogenicity.

KEYWORDS:

Functional characterization; Pompe disease; Splicing mutation

PMID:
30770309
DOI:
10.1016/j.nmd.2018.12.003

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