title: Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV.
abstract: A patient with mucolipidosis-IV heterozygous for two mutations in MCOLN1 expressed only her father's cDNA mutation c.1207C>T predicting an R403C change in mucolipin. She inherited a 93bp segment from mitochondrial NADH dehydrogenase 5 (MTND5) from her mother that was inserted in-frame prior to the last nucleotide of exon 2 of MCOLN1 (c.236_237ins93). This alteration abolished proper splicing of MCOLN1. The splice site at the end of the exon was not used due to an inhibitory effect of the inserted segment, resulting in two aberrant splice products containing stop codons in the downstream intron. These products were eliminated via nonsense-mediated decay. This is the first report of an inherited transfer of mitochondrial nuclear DNA causing a genetic disease. The elimination of the splice site by the mitochondrial DNA requires a change in splicing prediction models.
authors.affiliation: Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892-1260, USA. goldine@ninds.nih.gov
authors.forename: Ehud
authors.initials: E
authors.lastname: Goldin
authors.forename: Stefanie
authors.initials: S
authors.lastname: Stahl
authors.forename: Adele M
authors.initials: AM
authors.lastname: Cooney
authors.forename: Christine R
authors.initials: CR
authors.lastname: Kaneski
authors.forename: Surya
authors.initials: S
authors.lastname: Gupta
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: James R
authors.initials: JR
authors.lastname: Ellis
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D004272:DNA, Mitochondrial; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009081:Mucolipidoses / Q000235:genetics*; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D012326:RNA Splicing / Q000235:genetics; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels
chemical_list: D018076:DNA, Complementary; D004272:DNA, Mitochondrial; C416674:MCOLN1 protein, human; D008565:Membrane Proteins; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels