A novel mutation in the SERAC1 gene correlates with the severe manifestation of the MEGDEL phenotype, as revealed by whole‑exome sequencing

Alagoz,Meryem; Kherad,Nasim; Turkmen,Selda; Bulut,Hatice; Yuksel,Adnan

doi:10.3892/etm.2020.8658

A novel mutation in the SERAC1 gene correlates with the severe manifestation of the MEGDEL phenotype, as revealed by whole‑exome sequencing

Authors:
- Meryem Alagoz
- Nasim Kherad
- Selda Turkmen
- Hatice Bulut
- Adnan Yuksel
View Affiliations

Affiliations: Department of Molecular Biology and Genetics, Genome Centre, Biruni University, Istanbul 34010, Turkey, Department of Medical Biology, Istanbul Cerrahpasa University, Istanbul 34096, Turkey, Faculty of Medicine, Biruni University Hospital, Istanbul 34010, Turkey
Published online on: April 9, 2020 https://doi.org/10.3892/etm.2020.8658
Pages: 3505-3512
Copyright: © Alagoz et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The condition 3-methylglutaconic aciduria (3‑MGA) with deafness, encephalopathy and Leigh-like (MEGDEL) syndrome, also known as 3‑MGA IV, is one of a group of five rare metabolic disorders characterized by mitochondrial dysfunction, resulting in a series of phenotypic abnormalities. It is a rare, recessive inherited disorder with a limited number of cases reported worldwide; hence, it is important to study each case to understand its genetic complexity. An impaired activity of serine active site‑containing protein 1 (SERAC1), caused by mutations, leads to defects in phosphatidylglycerol remodelling, which is important for mitochondrial function and intracellular cholesterol trafficking. In the present study, the patients (two male siblings of consanguineous Turkish parents) were analysed, whose multisystem dysfunctions, including an elevated 3‑MGA concentration in early age, hearing loss and Leigh‑like syndrome as determined by MRI, were consistent with MEGDEL syndrome. A novel mutation in the SERAC1 gene, in the upstream lipase domain, c.1015G>C (p.Gly339Arg) mutation located on exon 10 of the SERAC1, was identified and predicted to cause protein dysfunction. Furthermore, the results pointed towards a possible association between this mutation and the severity of MEGDEL syndrome.

View Figures

View References

1	Roeben B, Schüle R, Ruf S, Bender B, Alhaddad B, Benkert T, Meitinger T, Reich S, Böhringer J, Langhans CD, et al: SERAC1 deficiency causes complicated HSP: Evidence from a novel splice mutation in a large family. J Med Genet. 55:39–47. 2018.PubMed/NCBI View Article : Google Scholar
2	Wortmann S, Rodenburg RJ, Huizing M, Loupatty FJ, de Koning T, Kluijtmans LA, Engelke U, Wevers R, Smeitink JA and Morava E: Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation. Mol Genet Metab. 88:47–52. 2006.PubMed/NCBI View Article : Google Scholar
3	Wortmann SB, Vaz FM, Gardeitchik T, Vissers LE, Renkema GH, Schuurs-Hoeijmakers JH, Kulik W, Lammens M, Christin C, Kluijtmans LA, et al: Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet. 44:797–802. 2012.PubMed/NCBI View Article : Google Scholar
4	Sarig O, Goldsher D, Nousbeck J, Fuchs-Telem D, Cohen-Katsenelson K, Iancu TC, Manov I, Saada A, Sprecher E and Mandel H: Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1. Am J Med Genet A. 161A:2204–2215. 2013.PubMed/NCBI View Article : Google Scholar
5	Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S, Alhaddad B, AlSayed M, Al-Owain MA, Al-Zaidan HI, Balasubramaniam S, Barić I, Bubshait DK, et al: Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases. Ann Neurol. 82:1004–1015. 2017.PubMed/NCBI View Article : Google Scholar
6	Radha Rama Devi A and Lingappa L: Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability. Eur J Med Genet. 61:100–103. 2018.PubMed/NCBI View Article : Google Scholar
7	IJlst L1. Loupatty FJ, Ruiter JP, Duran M, Lehnert W and Wanders RJ: 3-Methylglutaconic aciduria type I is caused by pathogenic variants in AUH. Am J Hum Genet. 71:1463–1466. 2002.PubMed/NCBI View Article : Google Scholar
8	Wortmann SB, Kluijtmans LA, Engelke UF, Wevers RA and Morava E: The 3-methylglutaconic acidurias: What's new? J Inherit Metab Dis. 35:13–22. 2012.PubMed/NCBI View Article : Google Scholar
9	Wortmann SB, Rodenburg RJT, Jonckheere A, de Vries MC, Huizing M, Heldt K, van den Heuvel LP, Wendel U, Kluijtmans LA, Engelke UF, et al: Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: A diagnostic strategy. Brain. 132:136–146. 2009.PubMed/NCBI View Article : Google Scholar
10	Houtkooper RH, Turkenburg M, Poll-The BT, Karall D, Pérez-Cerdá C, Morrone A, Malvagia S, Wanders RJ, Kulik W and Vaz FM: The enigmatic role of tafazzin in cardiolipin metabolism. Biochim Biophys Acta. 1788:2003–2014. 2009.PubMed/NCBI View Article : Google Scholar
11	Xu Y, Kelley RI, Blanck TJ and Schlame M: Remodeling of cardiolipin by phospholipid transacylation. J Biol Chem. 278:51380–51385. 2003.PubMed/NCBI View Article : Google Scholar
12	Bione S, D'Adamo P, Maestrini E, Gedeon AK, Bolhuis PA and Toniolo D: A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet. 12:385–389. 1996.PubMed/NCBI View Article : Google Scholar
13	Whited K, Baile MG, Currier P and Claypool SM: Seven functional classes of Barth syndrome mutation. Hum Mol Genet. 22:483–492. 2013.PubMed/NCBI View Article : Google Scholar
14	Schlame M, Kelley RI, Feigenbaum A, Towbin JA, Heerdt PM, Schieble T, Wanders RJ, DiMauro S and Blanck TJ: Phospholipid abnormalities in children with Barth syndrome. J Am Coll Cardiol. 42:1994–1999. 2003.PubMed/NCBI View Article : Google Scholar
15	Vreken P, Valianpour F, Nijtmans LG, Grivell LA, Plecko B, Wanders RJ and Barth PG: Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome. Biochem Biophys Res Commun. 279:378–382. 2000.PubMed/NCBI View Article : Google Scholar
16	Costeff H, Elpeleg O, Apter N, Divry P and Gadoth N: 3-Methylglutaconic aciduria in ‘optic atrophy plus’. Ann Neurol. 33:103–104. 1993.PubMed/NCBI View Article : Google Scholar
17	Elpeleg ON, Costeff H, Joseph A, Shental Y, Weitz R and Gibson KM: 3-Methylglutaconic aciduria in the Iraqi-Jewish ‘optic atrophy plus’ (Costeff) syndrome. Dev Med Child Neurol. 36:167–172. 1994.PubMed/NCBI View Article : Google Scholar
18	Nystuen A, Costeff H, Elpeleg ON, Apter N, Bonné-Tamir B, Mohrenweiser H, Haider N, Stone EM and Sheffield VC: Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene. Hum Mol Genet. 6:563–569. 1997.PubMed/NCBI View Article : Google Scholar
19	Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ and Bernier FP: Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. J Med Genet. 43:385–393. 2006.PubMed/NCBI View Article : Google Scholar
20	Ojala T, Polinati P, Manninen T, Hiippala A, Rajantie J, Karikoski R, Suomalainen A and Tyni T: New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies. Pediatr Res. 72:432–437. 2012.PubMed/NCBI View Article : Google Scholar
21	Tort F, García-Silva MT, Ferrer-Cortès X, Navarro-Sastre A, Garcia-Villoria J, Coll MJ, Vidal E, Jiménez-Almazán J, Dopazo J, Briones P, et al: Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. Mol Genet Metab. 110:73–77. 2013.PubMed/NCBI View Article : Google Scholar
22	Bonnefond A, Philippe J, Durand E, Dechaume A, Huyvaert M, Montagne L, Marre M, Balkau B, Fajardy I, Vambergue A, et al: Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One. 7(e37423)2012.PubMed/NCBI View Article : Google Scholar