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

• 影响指数: 4.534
• 发表时间: 05 2017
• 来源期刊: Mitochondrion
• DOI: 10.1016/j.mito.2017.02.004
• PMID: 28216230
• 文章类型: Case Reports
• 中科院分区: Q3
• 方向: 生物
• 作者列表: Simon MT,Ng BG,Friederich MW,Wang RY,Boyer M,Kircher M,Collard R,Buckingham KJ,Chang R,Shendure J,Nickerson DA,Bamshad MJ, ,Van Hove JLK,Freeze HH,Abdenur JE

关键词: Congenital disorders of glycosylation; Cryptic splice site; GFM1; Mitochondrial disease; Mitochondrial elongation factor

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

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.