Cytochrome C oxydase deficiency: SURF1 gene investigation in patients with Leigh syndrome

Maâlej, M.; Kammoun, T.; Alila-Fersi, Olfa; Kharrat, M.; Ammar, Marwa; Felhi, Rahma; Mkaouar-Rebai, Emna; Keskes, Leila; Hachicha, M.; Fakhfakh, Faiza

doi:10.1016/j.bbrc.2018.02.169

Cited by 8 publications

(2 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the vital importance of SURF1 in the human COX assembly, human SURF1 gene defects result in the failure of active COX formation and accumulation of COX assembly intermediates in tissues. Pathogenic SURF1 variants usually present with Leigh Syndrome (LS) and are the most common cause of COX deficiency-associated LS (I.-C. [ 11 , 13 ]). SURF1 is necessary for correct COX assembly and a defect of this assembly factor was the first example of an indirect effect causing LS [ 27 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

SURF1 related Leigh syndrome: Clinical and molecular findings of 16 patients from Turkey

Köse

Canda

Kağnıcı

et al. 2020

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

Introduction Pathogenic variants in SURF1 , a nuclear-encoded gene encoding a mitochondrial chaperone involved in COX assembly, are one of the most common causes of Leigh syndrome (LS). Material-methods Sixteen patients diagnosed to have SURF1 -related LS between 2012 and 2020 were included in the study. Their clinical, biochemical and molecular findings were recorded. 10/16 patients were diagnosed using whole-exome sequencing (WES), 4/16 by Sanger sequencing of SURF1 , 1/16 via targeted exome sequencing and 1/16 patient with whole-genome sequencing (WGS). The pathogenicity of SURF1 variants was evaluated by phylogenetic studies and modelling on the 3D structure of the SURF1 protein. Results We identified 16 patients from 14 unrelated families who were either homozygous or compound heterozygous for SURF1 pathogenic variants. Nine different SURF1 variants were detected The c.769G > A was the most common variant with an allelic frequency of 42.8% (12/28), c.870dupT [(p.Lys291*); (8/28 28.5%)], c.169delG [(p.Glu57Lysfs*15), (2/24; 7.1%)], c.532 T > A [(p.Tyr178Asn); (2/28, 7.1%)], c.653_654delCT [(p.Pro218Argfs*29); (4/28, 14.2%)] c.595_597delGGA [(p.Gly199del); (1/28, 3.5%)], c.751 + 1G > A (2/28, 4.1%), c.356C > T [(p.Pro119Leu); (2/28, 3.5%)] were the other detected variants. Two pathogenic variants, C.595_597delGGA and c.356C > T, were detected for the first time. The c.769 G > A variant detected in 6 patients from 5 families was evaluated in terms of phenotype-genotype correlation. There was no definite genotype – phenotype correlation. Conclusions To date, more than 120 patients of LS with SURF1 pathogenic variants have been reported. We shared the clinical, molecular data and natural course of 16 new SURF1 defect patients from our country. This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the SURF1 gene. The identification of common variants and phenotype of the SURF1 gene is important for understanding SURF1 related LS. Synopsis SURF1 gene defects are one of the most important causes of LS; patients have a homogeneous clinical and biochemical phenotype.

show abstract

Section: Introductionmentioning

confidence: 99%

SURF1 related Leigh syndrome: Clinical and molecular findings of 16 patients from Turkey

Köse

Canda

Kağnıcı

et al. 2020

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

show abstract

“…Two novel mitochondrial variants, m.5523T>G and m.5559A>G located in MT-TW affecting conserved regions of the tRNA trp , were also identified [ 11 ] as well as the m.9478T>C missense variant (V91A) in COXIII [ 12 ]. Alternatively, variants in SURF1 were identified, either as a homozygous splice site c.516-517delAG or as compound heterozygous c.752-18A>C plus c.751+16G>A, most probably altering SURF1 mRNA splicing and consequently the abundance of SURF1 protein [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment

et al. 2022

View full text Add to dashboard Cite

Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of this study consisted in defining the molecular diagnosis of a group of Tunisian patients with LS. Six children, belonging to five Tunisian families, with clinical and imaging presentations suggestive of LS were recruited. Whole mitochondrial DNA and targeted next generation sequencing of a panel of 281 nuclear genes involved in mitochondrial physiology were performed. Bioinformatic analyses were achieved in order to identify deleterious variations. A single m.10197G>A (p.Ala47Thr) variant was found in the mitochondrial MT-ND3 gene in one patient, while the others were related to autosomal homozygous variants: two c.1412delA (p.Gln471ArgfsTer42) and c.1264A>G (p.Thr422Ala) in SLC19A3, one c.454C>G (p.Pro152Ala) in SLC25A19 and one c.122G>A (p.Gly41Asp) in ETHE1. Our findings demonstrate the usefulness of genomic investigations to improve LS diagnosis in consanguineous populations, and further allow for treating the patients harboring variants in SLC19A3 and SLC25A19 that contribute to thiamine transport, by thiamine and biotin supplementation. Considering the Tunisian genetic background, the newly identified variants could be screened in patients with similar clinical presentation in related populations.

show abstract

SURF1 Deficiency: Expanding on Disease Phenotype and Assessing Disease Burden by Describing Clinical and Biochemical Phenotype

Kayani,

Daescu,

Dahshi

et al. 2024

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Leigh syndrome, a severe neurological disorder is commonly caused by homozygous or bi‐allelic pathogenic variants in the SURF1 gene. SURF1 deficiency leads to dysfunction of Cytochrome C Oxidase (COX) activity, which is crucial for mitochondrial oxidative phosphorylation. Understanding COX activity's correlation with disease severity is essential for developing SURF1 Leigh Syndrome biomarkers. This study assesses the disease burden in SURF1 Leigh Syndrome and evaluates COX activity as a treatment biomarker. We reviewed records and questionnaires from 17 individuals, classifying them into phenotypic and genotypic groups. We compared COX activity assays in patient fibroblasts to age‐matched controls, clinical data, and neuroimaging findings. Patient COX activity was at most 50% of controls, averaging 32% (p < 0.001). Common clinical features included brainstem abnormalities (93.3%), motor regression (92.3%), bi‐allelic heterozygous SURF1 variants (88.2%), and delayed growth/development (35.7%). Homozygous and heterozygous nonsense/frameshift variants showed more severe phenotypes (p = 0.008) and more MRI abnormalities (p = 0.005). Significant COX activity reduction is linked to SURF1 Leigh Syndrome, with genotype influencing disease severity. Clinical and neuroimaging correlations show potential for prognostic indicators. This study lays the groundwork for future research and clinical application of COX activity as a SURF1 Leigh Syndrome biomarker.

show abstract

Cytochrome C oxydase deficiency: SURF1 gene investigation in patients with Leigh syndrome

Cited by 8 publications

References 29 publications

SURF1 related Leigh syndrome: Clinical and molecular findings of 16 patients from Turkey

SURF1 related Leigh syndrome: Clinical and molecular findings of 16 patients from Turkey

Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment

SURF1 Deficiency: Expanding on Disease Phenotype and Assessing Disease Burden by Describing Clinical and Biochemical Phenotype

Contact Info

Product

Resources

About