Characterization of two novel intronic OPA1 mutations resulting in aberrant pre-mRNA splicing

Background We report two novel splice region mutations in OPA1 in two unrelated families presenting with autosomal-dominant optic atrophy type 1 (ADOA1) (ADOA or Kjer type optic atrophy). Mutations in OPA1 encoding a mitochondrial inner membrane protein are a major cause of ADOA. Methods We analyzed...

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Bibliographic Details
Published in:	BMC medical genetics Vol. 18; no. 1; p. 22
Main Authors:	Bolognini, Ramona, Gerth-Kahlert, Christina, Abegg, Mathias, Bartholdi, Deborah, Mathis, Nicolas, Sturm, Veit, Gallati, Sabina, Schaller, André
Format:	Journal Article
Language:	English
Published:	London BioMed Central 28.02.2017
Subjects:	Atrophy Base Sequence Biomedical and Life Sciences Biomedicine Blindness Clinical-Molecular Genetics and Cytogenetics Cytogenetics DNA - chemistry DNA - isolation & purification DNA - metabolism DNA Mutational Analysis Exons Families & family life Gene Function Genetic testing GTP Phosphohydrolases - genetics Heterozygote Human Genetics Humans INDEL Mutation Introns Mitochondrial DNA Mutation Optic Atrophy, Autosomal Dominant - genetics Optics Parents & parenting Patients Pedigree Proteins Research Article Retina - diagnostic imaging RNA Precursors - genetics RNA Precursors - metabolism RNA Splicing Tomography Tomography, Optical Coherence Visual acuity Visual impairment Optic neuropathies Splice site mutation Autosomal dominant optic atrophy OPA1 Kjer type optic atrophy
ISSN:	1471-2350, 1471-2350
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Summary:	Background We report two novel splice region mutations in OPA1 in two unrelated families presenting with autosomal-dominant optic atrophy type 1 (ADOA1) (ADOA or Kjer type optic atrophy). Mutations in OPA1 encoding a mitochondrial inner membrane protein are a major cause of ADOA. Methods We analyzed two unrelated families including four affected individuals clinically suspicious of ADOA. Standard ocular examinations were performed in affected individuals of both families. All coding exons, as well as exon-intron boundaries of the OPA1 gene were sequenced. In addition, multiplex ligation-dependent probe amplification (MLPA) was performed to uncover copy number variations in OPA1 . mRNA processing was monitored using RT-PCR and subsequent cDNA analysis. Results We report two novel splice region mutations in OPA1 in two unrelated individuals and their affected relatives, which were previously not described in the literature. In one family the heterozygous insertion and deletion c.[611-37_611-38insACTGGAGAATGTAAAGGGCTTT;611-6_611-16delCATATTTATCT] was found in all investigated family members leading to the activation of an intronic cryptic splice site. In the second family sequencing of OPA1 disclosed a de novo heterozygous deletion c.2012+4_2012+7delAGTA resulting in exon 18 and 19 skipping, which was not detected in healthy family members. Conclusion We identified two novel intronic mutations in OPA1 affecting the correct OPA1 pre-mRNA splicing, which was confirmed by OPA1 cDNA analysis. This study shows the importance of transcript analysis to determine the consequences of unclear intronic mutations in OPA1 in proximity to the intron-exon boundaries.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1471-2350 1471-2350
DOI:	10.1186/s12881-017-0383-x