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. 2020 Oct 23:25:100657.
doi: 10.1016/j.ymgmr.2020.100657. eCollection 2020 Dec.

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

Melis Kose  1   2   3 , Ebru Canda  2 , Mehtap Kagnici  4 , Ayça Aykut  5 , Ogün Adebali  6 , Asude Durmaz  5 , Aylin Bircan  6 , Gulden Diniz  7 , Cenk Eraslan  8 , Engin Kose  9 , Aycan Ünalp  10 , Ünsal Yılmaz  10 , Berk Ozyilmaz  11 , Taha Reşid Özdemir  11 , Tahir Atik  2 , Sema Kalkan Uçar  2 , Robert McFarland  12 , Robert W Taylor  12 , Garry K Brown  3 , Mahmut Çoker  2 , Ferda Özkınay  2   4
Affiliations

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

Melis Kose et al. Mol Genet Metab Rep. .

Abstract

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.

Keywords: COX deficiency; Leigh syndrome; Neuroregression; Next-generation sequencing; Nuclear mitochondrial disorders; SURF1 gene.

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Figures

Fig. 1
Fig. 1
: SURF1 structure prediction. (A) Secondary structure of human SURF1 predicted by PSIPRED at top, and below secondary structure corresponds to tertiary structure generated by trRosetta are shown. Pink and green regions are predicted to be alpha-helices and beta-sheets, respectively. The uncolored gray regions correspond to the disordered regions. Pinpointed mutations reported in this study are colored and shaped based on their mutation types and novelty. (B) The tertiary structure of SURF1 built with trRosetta. Novel missense mutation p.119 is shown as red spheres, and previously annotated missense mutations p.178, p.256 are shown as green spheres. Annotated frameshift mutations p.1, p.57, p.218, and novel deletion p.199 are shown as orange.
Fig. 2
Fig. 2
Conservation of the frequent alleles and phenotype-associated positions through phylogenetic analysis. (A) Allele frequency of observed population variants in human Surf1 protein. The variants that are more frequent than 0.1% in the population are reported only. (B) Conservation of each position in mammals. The positions with observed mutations are highlighted with the consistent color and shape scheme in Fig. 1A. (C) Maximum likelihood tree built with RAxML is shown along with multiple sequence alignment. The local multiple sequence alignment of the positions for the novel missense and frameshift mutations are plotted. Some clades are collapsed for visual purposes, the full tree and multiple sequence alignment is given in the supplementary figures.
Fig. 2
Fig. 2
Conservation of the frequent alleles and phenotype-associated positions through phylogenetic analysis. (A) Allele frequency of observed population variants in human Surf1 protein. The variants that are more frequent than 0.1% in the population are reported only. (B) Conservation of each position in mammals. The positions with observed mutations are highlighted with the consistent color and shape scheme in Fig. 1A. (C) Maximum likelihood tree built with RAxML is shown along with multiple sequence alignment. The local multiple sequence alignment of the positions for the novel missense and frameshift mutations are plotted. Some clades are collapsed for visual purposes, the full tree and multiple sequence alignment is given in the supplementary figures.
Fig. 2
Fig. 2
Conservation of the frequent alleles and phenotype-associated positions through phylogenetic analysis. (A) Allele frequency of observed population variants in human Surf1 protein. The variants that are more frequent than 0.1% in the population are reported only. (B) Conservation of each position in mammals. The positions with observed mutations are highlighted with the consistent color and shape scheme in Fig. 1A. (C) Maximum likelihood tree built with RAxML is shown along with multiple sequence alignment. The local multiple sequence alignment of the positions for the novel missense and frameshift mutations are plotted. Some clades are collapsed for visual purposes, the full tree and multiple sequence alignment is given in the supplementary figures.
Fig. 3
Fig. 3
A Age at onset, neurodegeneration and initial symptoms of the patients. ED: Episodic decompensation, FD: Feeding difficulty, Hyp: Hypotonicity, ND: Neurodegeneration, SZ: Seizure, Dys: Dystonia, GF: Growth failure, Atx: Ataxia, DD; Developmental delay. B Serum lactate and episodic decompensation attacks of the patients.
Fig. 3
Fig. 3
A Age at onset, neurodegeneration and initial symptoms of the patients. ED: Episodic decompensation, FD: Feeding difficulty, Hyp: Hypotonicity, ND: Neurodegeneration, SZ: Seizure, Dys: Dystonia, GF: Growth failure, Atx: Ataxia, DD; Developmental delay. B Serum lactate and episodic decompensation attacks of the patients.
Fig. 4
Fig. 4
Phenotypic Features of Patients. P2: Global hypertrichosis concentrated in back, large mongolian spot on gluteus P7: Microcephaly, narrow forehead,low-set ears, hypertelorism, depressed nasal bridge, short and bulbous nose, anteverted nostrils, smooth-broad philtrum, thin lips, down-thurned mouth, hypretrichosis on extremities P9: Narrow forehead, prominent eyebrows, downslanted palpebral fissures, low-set ears, smooth-broad philtrum, thin lips, micrognathia, pectus excavatum, hypertrichosis. P11: Narrow forehead, prominent eyebrows, low-set ears, thin lips, down-thurned mouth, low hair line, hypertrichosis concentrated on nape of head and back. P13: Narrow forehead, depressed nasal bridge, short-bulbous nose, thin lips, broad chest. P14: Narrow forehead, hypertelorism, depressed nasal bridge, thin lips,large mongolian spots on forehead and gluteus.
Fig. 5
Fig. 5
A. Kaplan-Meier survival (hypotonicity). B. Kaplan-Meier survival (feeding difficulty).
Fig. 5
Fig. 5
A. Kaplan-Meier survival (hypotonicity). B. Kaplan-Meier survival (feeding difficulty).
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References

    1. Altschul S.F., Gish W., Miller W., Myers E.W., Lipman D.J. Basic local alignment search tool. J. Mol. Biol. 1990;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. - DOI - PubMed
    1. Baertling F., Rodenburg R.J., Schaper J., Smeitink J.A., Koopman W.J.H., Mayatepek E., Morava E., Distelmaier F. A guide to diagnosis and treatment of Leigh syndrome. J. Neurol. Neurosurg. Psychiatry. 2014;85(3):257–265. doi: 10.1136/jnnp-2012-304426. - DOI - PubMed
    1. Diniz G., Tosun Yildirim H., Unalp A., Barutcuoglu M., Guzel O., Polat M., Ture S., Ozgonul F., Serdaroglu G. The evaluation of muscle biopsy findings in children with neuromuscular disorders. J. Dr. Behcet Uz Child. Hosp. 2013;2(2):62–67. doi: 10.5222/buchd.2012.062. - DOI
    1. Dınız G., Hazan F., Yildirim H.T., Unalp A., Polat M., Serdaroğlu G., Güzel O., Bağ O., Seçıl Y., Ozgönül F., Türe S., Akhan G., Tükün A. Histopathological and genetic features of patients with limb girdle muscular dystrophy type 2C. Turk Patoloji Dergisi. 2014;30(2):111–117. doi: 10.5146/tjpath.2014.01239. - DOI - PubMed
    1. Grant B.J., Rodrigues A.P.C., ElSawy K.M., McCammon J.A., Caves L.S.D. Bio3d: an R package for the comparative analysis of protein structures. Bioinformatics (Oxford, England) 2006;22(21):2695–2696. doi: 10.1093/bioinformatics/btl461. - DOI - PubMed

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