Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency

Mariella T Simon; Bobby G Ng; Marisa W Friederich; Raymond Y Wang; Monica Boyer; Martin Kircher; Renata Collard; Kati J Buckingham; Richard Chang; Jay Shendure; Deborah A Nickerson; Michael J Bamshad; University of Washington Center for Mendelian Genomics; Johan L K Van Hove; Hudson H Freeze; Jose E Abdenur

doi:10.1016/j.mito.2017.02.004

Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency

Mitochondrion. 2017 May:34:84-90. doi: 10.1016/j.mito.2017.02.004. Epub 2017 Feb 12.

Authors

Mariella T Simon¹, Bobby G Ng², Marisa W Friederich³, Raymond Y Wang⁴, Monica Boyer⁵, Martin Kircher⁶, Renata Collard³, Kati J Buckingham⁷, Richard Chang⁴, Jay Shendure⁸, Deborah A Nickerson⁶, Michael J Bamshad⁹; University of Washington Center for Mendelian Genomics; Johan L K Van Hove³, Hudson H Freeze², Jose E Abdenur¹⁰

Affiliations

¹ Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA; Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA.
² Human Genetics Program, Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA.
³ Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
⁴ Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA; Department of Pediatrics, University of California Irvine, Irvine, CA, USA.
⁵ Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA.
⁶ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
⁷ Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁸ Department of Genome Sciences, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
⁹ Department of Genome Sciences, University of Washington, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁰ Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA; Department of Pediatrics, University of California Irvine, Irvine, CA, USA. Electronic address: jabdenur@choc.org.

Abstract

We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.

Keywords: Congenital disorders of glycosylation; Cryptic splice site; GFM1; Mitochondrial disease; Mitochondrial elongation factor.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Child
Child, Preschool
Congenital Abnormalities / genetics*
Congenital Abnormalities / pathology*
Gene Expression*
Humans
Infant
Infant, Newborn
Male
Mitochondrial Proteins / biosynthesis*
Mitochondrial Proteins / genetics*
Oxidative Phosphorylation*
Peptide Elongation Factor G / biosynthesis*
Peptide Elongation Factor G / genetics*
RNA Splice Sites*

Substances

GFM1 protein, human
Mitochondrial Proteins
Peptide Elongation Factor G
RNA Splice Sites

Abstract

Publication types

MeSH terms

Substances

Grants and funding