期刊
HUMAN MUTATION
卷 41, 期 2, 页码 403-411出版社
WILEY-HINDAWI
DOI: 10.1002/humu.23938
关键词
alternative splicing; arthrogryposis; congenital titinopathies; intronic splice variant; TTN metatranscript-only
资金
- National Health and Medical Research Council of Australia [APP1048816, APP1136197, APP1080587]
- Muscular Dystrophy New South Wales PhD scholarship
- National Institute of Neurological Disorders and Stroke, of the National Institutes of Health
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung and Blood Institute [UM1 HG008900]
- National Human Genome Research Institute [R01 HG009141]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [ZIANS003129] Funding Source: NIH RePORTER
We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3 ' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate >= 66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.
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