SURF1 explained

Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene.^{[1] [2]} The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex), which is involved in the regulation of cytochrome c oxidase assembly.^{[3] [4]} Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase (complex IV) deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).^{[5] [6]}

Structure

SURF1 is located on the q arm of chromosome 9 in position 34.2 and has 9 exons. The SURF1 gene produces a 33.3 kDa protein composed of 300 amino acids.^{[7] [8]} The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. SURF1 is a multi-pass protein that contains two transmembrane regions, one 19 amino acids in length from positions 61-79 and the other 17 amino acids in length from positions 274–290.

Function

This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. SURF1 is a multi-pass membrane protein component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex). The MITRAC complex regulates cytochrome c oxidase assembly by acting as a central assembly intermediate, receiving subunits imported to the inner mitochondrial membrane and regulating COX1 mRNA translation.^[9]

Clinical significance

Mutations in SURF1 have been associated with mitochondrial complex IV (cytochrome c oxidase) deficiency with clinical manifestations of Leigh syndrome and Charcot-Marie-Tooth disease 4K (CMT4K).^[10]

Mitochondrial complex IV deficiency

Mitochondrial complex IV deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. In patients presenting with pathogenic mutations resulting in dysfunctioning SURF1, cytochrome c oxidase activity is likely to be diminished in one or more types of tissues.^[11]

Leigh syndrome

Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. There have been over 30 different mutations in SURF1 that have been associated with Leigh syndrome. These mutations, which comprise at least 10 missense or nonsense, 8 splice site, and 12 insertion or deletion mutations, are believed to be the result of dysfunctional SURF1 that results in Leigh syndrome and cytochrome c oxidase deficiency. The most common mutation is believed to be 312_321del 311_312insAT.

Charcot-Marie-Tooth disease 4K (CMT4K)

Charcot-Marie-Tooth disease 4K (CMT4K) is an autosomal recessive, demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention, autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4K patients manifest upper and lower limbs involvement. Some affected individuals have nystagmus, polyneuropathy, putaminal and periaqueductal lesions, and late-onset cerebellar ataxia. This disease, when associated with mutations in SURF1, has been found to be linked to cytochrome c oxidase deficiency. Variants associated with this CMT4K have included a homozygous splice site mutation, c.107-2A>G, a missense mutation, c.574C>T, and a deletion, c.799_800del.

Interactions

SURF1 has been shown to have 11 binary protein-protein interactions including 8 co-complex interactions. SURF1 interacts with COA3 as part of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex). PTGES3, SLC25A5, COX6C, COX14, COA1 have all also been found to interact with SURF1.^[12]

Further reading

• Shoubridge EA . Cytochrome c oxidase deficiency . American Journal of Medical Genetics . 106 . 1 . 46–52 . 2001 . 11579424 . 10.1002/ajmg.1378 .
• Lennard A, Gaston K, Fried M . The Surf-1 and Surf-2 genes and their essential bidirectional promoter elements are conserved between mouse and human . DNA and Cell Biology . 13 . 11 . 1117–26 . November 1994 . 7702754 . 10.1089/dna.1994.13.1117 .
• Duhig T, Ruhrberg C, Mor O, Fried M . The human Surfeit locus . Genomics . 52 . 1 . 72–8 . August 1998 . 9740673 . 10.1006/geno.1998.5372 .
• Yao J, Shoubridge EA . Expression and functional analysis of SURF1 in Leigh syndrome patients with cytochrome c oxidase deficiency . Human Molecular Genetics . 8 . 13 . 2541–9 . December 1999 . 10556303 . 10.1093/hmg/8.13.2541 . free .
• Teraoka M, Yokoyama Y, Ninomiya S, Inoue C, Yamashita S, Seino Y . Two novel mutations of SURF1 in Leigh syndrome with cytochrome c oxidase deficiency . Human Genetics . 105 . 6 . 560–3 . December 1999 . 10647889 . 10.1007/s004390051145 .
• Poyau A, Buchet K, Bouzidi MF, Zabot MT, Echenne B, Yao J, Shoubridge EA, Godinot C . Missense mutations in SURF1 associated with deficient cytochrome c oxidase assembly in Leigh syndrome patients . Human Genetics . 106 . 2 . 194–205 . February 2000 . 10746561 . 10.1007/s004390051028 . 1 November 2024 .
• Ogawa Y, Naito E, Ito M, Yokota I, Saijo T, Shinahara K, Kuroda Y . Three novel SURF-1 mutations in Japanese patients with Leigh syndrome . Pediatric Neurology . 26 . 3 . 196–200 . March 2002 . 11955926 . 10.1016/S0887-8994(01)00382-4 .
• Capková M, Hansíková H, Godinot C, Houst'ková H, Houstĕk J, Zeman J . [A new missense mutation of 574C>T in the SURF1 gene--biochemical and molecular genetic study in seven children with Leigh syndrome] . Casopis Lekaru Ceskych . 141 . 20 . 636–41 . October 2002 . 12515039 .
• Sacconi S, Salviati L, Sue CM, Shanske S, Davidson MM, Bonilla E, Naini AB, De Vivo DC, DiMauro S . Mutation screening in patients with isolated cytochrome c oxidase deficiency . Pediatric Research . 53 . 2 . 224–30 . February 2003 . 12538779 . 10.1203/01.PDR.0000048100.91730.6A . 11577/1368344 . 12496207 . free .
• Rossi A, Biancheri R, Bruno C, Di Rocco M, Calvi A, Pessagno A, Tortori-Donati P . Leigh Syndrome with COX deficiency and SURF1 gene mutations: MR imaging findings . AJNR. American Journal of Neuroradiology . 24 . 6 . 1188–91 . 2003 . 12812953 . 8148997 .
• Moslemi AR, Tulinius M, Darin N, Aman P, Holme E, Oldfors A . SURF1 gene mutations in three cases with Leigh syndrome and cytochrome c oxidase deficiency . Neurology . 61 . 7 . 991–3 . October 2003 . 14557577 . 10.1212/01.wnl.0000082391.98672.0a . 31028913 .
• Williams SL, Valnot I, Rustin P, Taanman JW . Cytochrome c oxidase subassemblies in fibroblast cultures from patients carrying mutations in COX10, SCO1, or SURF1 . The Journal of Biological Chemistry . 279 . 9 . 7462–9 . February 2004 . 14607829 . 10.1074/jbc.M309232200 . free .
• Salviati L, Freehauf C, Sacconi S, DiMauro S, Thoma J, Tsai AC . Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome . American Journal of Medical Genetics. Part A . 128A . 2 . 195–8 . July 2004 . 15214016 . 10.1002/ajmg.a.30073 . 11577/1368341 . 19332655 . free .
• Smith D, Gray J, Mitchell L, Antholine WE, Hosler JP . Assembly of cytochrome-c oxidase in the absence of assembly protein Surf1p leads to loss of the active site heme . The Journal of Biological Chemistry . 280 . 18 . 17652–6 . May 2005 . 15764605 . 10.1074/jbc.C500061200 . free .
• Wilnai Y, Seaver LH, Enns GM . Atypical amyoplasia congenita in an infant with Leigh syndrome: a mitochondrial cause of severe contractures? . American Journal of Medical Genetics. Part A . 158A . 9 . 2353–7 . September 2012 . 22887355 . 10.1002/ajmg.a.35533 . 1163142 .
• Timothy J, Geller T . SURF-1 gene mutation associated with leukoencephalopathy in a 2-year-old . Journal of Child Neurology . 24 . 10 . 1296–301 . October 2009 . 19805825 . 10.1177/0883073809333543 . 8415901 .
• van Riesen AK, Antonicka H, Ohlenbusch A, Shoubridge EA, Wilichowski EK . Maternal segmental disomy in Leigh syndrome with cytochrome c oxidase deficiency caused by homozygous SURF1 mutation . Neuropediatrics . 37 . 2 . 88–94 . April 2006 . 16773507 . 10.1055/s-2006-924227 . 20192948 .
• Yüksel A, Seven M, Cetincelik U, Yeşil G, Köksal V . Facial dysmorphism in Leigh syndrome with SURF-1 mutation and COX deficiency . Pediatric Neurology . 34 . 6 . 486–9 . June 2006 . 16765830 . 10.1016/j.pediatrneurol.2005.10.020 .
• Coenen MJ, Smeitink JA, Farhoud MH, Nijtmans LG, Rodenburg R, Janssen A, van Kaauwen EP, Trijbels FJ, van den Heuvel LP . The first patient diagnosed with cytochrome c oxidase deficient Leigh syndrome: progress report . Journal of Inherited Metabolic Disease . 29 . 1 . 212–3 . February 2006 . 16601896 . 10.1007/s10545-006-0185-3 . 27796999 . free .
• Bruno C, Biancheri R, Garavaglia B, Biedi C, Rossi A, Lamba LD, Bado M, Greco M, Zeviani M, Minetti C . A novel mutation in the SURF1 gene in a child with Leigh disease, peripheral neuropathy, and cytochrome-c oxidase deficiency . Journal of Child Neurology . 17 . 3 . 233–6 . March 2002 . 12026244 . 10.1177/088307380201700318 . 27532055 .
• Williams SL, Taanman JW, Hansíková H, Houst'ková H, Chowdhury S, Zeman J, Houstek J . A novel mutation in SURF1 causes skipping of exon 8 in a patient with cytochrome c oxidase-deficient leigh syndrome and hypertrichosis . Molecular Genetics and Metabolism . 73 . 4 . 340–3 . August 2001 . 11509016 . 10.1006/mgme.2001.3206 .
• Rahman S, Brown RM, Chong WK, Wilson CJ, Brown GK . A SURF1 gene mutation presenting as isolated leukodystrophy . Annals of Neurology . 49 . 6 . 797–800 . June 2001 . 11409433 . 10.1002/ana.1060. 29980066 .
• Von Kleist-Retzow JC, Yao J, Taanman JW, Chantrel K, Chretien D, Cormier-Daire V, Rotig A, Munnich A, Rustin P, Shoubridge EA . Mutations in SURF1 are not specifically associated with Leigh syndrome . Journal of Medical Genetics . 38 . 2 . 109–13 . February 2001 . 11288709 . 1734810 . 10.1136/jmg.38.2.109 .
• Santoro L, Carrozzo R, Malandrini A, Piemonte F, Patrono C, Villanova M, Tessa A, Palmeri S, Bertini E, Santorelli FM . A novel SURF1 mutation results in Leigh syndrome with peripheral neuropathy caused by cytochrome c oxidase deficiency . Neuromuscular Disorders . 10 . 6 . 450–3 . August 2000 . 10899453 . 10.1016/s0960-8966(99)00122-4. 2885506 .

Notes and References

1. Yon J, Jones T, Garson K, Sheer D, Fried M . The organization and conservation of the human Surfeit gene cluster and its localization telomeric to the c-abl and can proto-oncogenes at chromosome band 9q34.1 . Human Molecular Genetics . 2 . 3 . 237–40 . March 1993 . 8499913 . 10.1093/hmg/2.3.237 .
2. Zhu Z, Yao J, Johns T, Fu K, De Bie I, Macmillan C, Cuthbert AP, Newbold RF, Wang J, Chevrette M, Brown GK, Brown RM, Shoubridge EA . SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome . Nature Genetics . 20 . 4 . 337–43 . December 1998 . 9843204 . 10.1038/3804 . 12584110 .
3. Web site: SURF1 - Surfeit locus protein 1 - Homo sapiens (Human) - SURF1 gene & protein. www.uniprot.org. en. 2018-08-07.
4. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
5. Web site: Entrez Gene: SURF1 surfeit 1.
6. Echaniz-Laguna A, Ghezzi D, Chassagne M, Mayençon M, Padet S, Melchionda L, Rouvet I, Lannes B, Bozon D, Latour P, Zeviani M, Mousson de Camaret B . SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease . Neurology . 81 . 17 . 1523–30 . October 2013 . 24027061 . 3888171 . 10.1212/WNL.0b013e3182a4a518 .
7. Web site: Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information. Yao. Daniel. amino.heartproteome.org. 2018-08-07. 2018-08-08. https://web.archive.org/web/20180808073130/https://amino.heartproteome.org/web/protein/Q15526. dead.
8. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
9. Dennerlein S, Oeljeklaus S, Jans D, Hellwig C, Bareth B, Jakobs S, Deckers M, Warscheid B, Rehling P . MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Checkpoint during Cytochrome c Oxidase Assembly . Cell Reports . 12 . 10 . 1644–55 . September 2015 . 26321642 . 10.1016/j.celrep.2015.08.009 . free . 11858/00-001M-0000-0028-466E-C . free .
10. Péquignot MO, Dey R, Zeviani M, Tiranti V, Godinot C, Poyau A, Sue C, Di Mauro S, Abitbol M, Marsac C . Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency . Human Mutation . 17 . 5 . 374–81 . May 2001 . 11317352 . 10.1002/humu.1112 . 26557551 .
11. Web site: Mitochondrial complex IV deficiency. www.uniprot.org. en. 2018-08-07.
12. Web site: IntAct Portal . IntAct. www.ebi.ac.uk. en. 2018-08-07.