Novel exon nucleotide substitution at the splice junction causes a neonatal Marfan syndrome.
The fibrillin-1 gene (FBN1) mutations are associated with a broad spectrum of disorders including Marfan syndrome (MFS) and show great clinical heterogeneity. An underrepresentation for mutations leading to premature termination codon (PTC) in FBN1 exons 24-32 was found in neonatal or severe MFS but the underlying cause was unclear. This study thoroughly examined two FBN1 mutations on exons 24-32 region to illustrate the molecular mechanisms underlying these FBN1 mutations on MFS etiology. Two nucleotide substitutions, c.3208G> C, the last nucleotide of exon 26, and c.3209A>G, the first nucleotide of exon 27, affecting the same amino acid, p.D1070H and p.D1070G, respectively, gave very different phenotypes. We demonstrate that c.3208G>C generates two alternatively spliced transcripts, while c.3209A>G does not affect the splicing. We further demonstrate that the aberrantly spliced transcripts do not go through nonsense-mediated decay, but rather produce unstable, premature protein peptides that are degraded by endoplasmic reticulum associated degradation. The molecular mechanism outlined here defines a model for the pathogenesis of PTC-containing mutation within the exons 24-32 of FBN1 in MFS. Furthermore, our data suggest that PTC mutation within this region may lead to early lethality in neonatal MFS.
Chao
S-C
SC
Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Douliou Branch, Yunlin, Taiwan.
Chen
J-S
JS
Tsai
C-H
CH
Lin
Jy-M
JM
Lin
Y-J
YJ
Sun
H S
HS
D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D018389:Codon, Nonsense / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007231:Infant, Newborn; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008382:Marfan Syndrome / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009711:Nucleotides / Q000235:genetics*; D011247:Pregnancy; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D022821:RNA Splice Sites / Q000187:drug effects / Q000235:genetics*; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics; D054392:Adipokines
D018389:Codon, Nonsense; D000071838:Fibrillin-1; D000071837:Fibrillins; D007976:Leupeptins; D008840:Microfilament Proteins; D050505:Mutant Proteins; D009711:Nucleotides; D022821:RNA Splice Sites; C000605722:FBN1 protein, human; D054392:Adipokines; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde