Surfeit human gene cluster

January 4, 2023
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Surfeit is a human gene cluster that consists of a group of very tightly linked genes on chromosome 9 that do not share sequence similarity. Genes in this cluster are numbered 1 through 6: SURF1, SURF2, SURF3, SURF4, SURF5, and SURF6.

Surfeit locus protein 1 (SURF1)

Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1gene. 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. 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).

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. 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.

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).

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.[15][7][8]

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.

SURF2

SURF2 is a protein which in humans is encoded by the SURF2gene.SURF2 is a member of the surfeit gene family. The SURF2 molecule interacts with beta-1, 4-Gal-T3, uPAR, and WDR20. As part of the surfeit gene cluster, SURF2 is one of several tightly linked genes that do not share sequence similarity. SURF2 maps to human chromosome 9q34.2 and shares a bidirectional promoter with SURF1 on the opposite strand. A bidirectional promoter activity is expected in the intergenic region between SURF1 and SURF2, as seen in mice.

60S ribosomal protein L7a (REDIRECTED FROM SURF3)

60S ribosomal protein L7a is a protein that in humans is encoded by the RPL7A gene.

Cytoplasmic ribosomes, organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L7AE family of ribosomal proteins. It can interact with a subclass of nuclear hormone receptors, including thyroid hormone receptor, and inhibit their ability to transactivate by preventing their binding to their DNA response elements. This gene is included in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity. It is co-transcribed with the U24, U36a, U36b, and U36c small nucleolar RNA genes, which are located in its second, fifth, fourth, and sixth introns, respectively. This gene rearranges with the trk proto-oncogene to form the chimeric oncogene trk-2h, which encodes an oncoprotein consisting of the N terminus of ribosomal protein L7a fused to the receptor tyrosine kinase domain of trk. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.

  • Ziemiecki A, Muller RG, Fu XC, Hynes NE, Kozma S (Feb 1990). “Oncogenic activation of the human trk proto-oncogene by recombination with the ribosomal large subunit protein L7a“. EMBO J. 9 (1): 191–6. doi:10.1002/j.1460-2075.1990.tb08095.x. PMC 551645. PMID 2403926.
  • Kozma SC, Redmond SM, Fu XC, Saurer SM, Groner B, Hynes NE (May 1988). “Activation of the receptor kinase domain of the trk oncogene by recombination with two different cellular sequences“. EMBO J. 7 (1): 147–54. doi:10.1002/j.1460-2075.1988.tb02794.x. PMC 454232. PMID 2966065.
  • “Entrez Gene: RPL7A ribosomal protein L7a“.

In molecular biology, U24 is a member of the C/D class of snoRNA which contain the C (UGAUGA) and D (CUGA) box motifs. C/D box snoRNAs have been shown to act as methylation guides for a number of RNA targets. U24 is encoded within an intron of the gene for ribosomal protein L7a in mammals, chicken and Fugu. The U76/SNORD76 snoRNA is found in an intron of the uRNA host gene (UHG) growth arrest specific 5 (GAS5) transcript gene. snoRNAs Z20 and U76 snoRNAs show clear similarity to U24. An experiment that looked at 22 different non-small-cell lung cancer tissues found that SNORD33, SNORD66 and SNORD76 were over-expressed relative to matched noncancerous lung tissues.

In molecular biology, snoRNA U36 (also known as SNORD36) is a non-coding RNA (ncRNA) molecule which functions in the biogenesis (modification) of other small nuclear RNAs (snRNAs). This type of modifying RNA is located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis. It is known as a small nucleolar RNA (snoRNA) and also often referred to as a guide RNA. snoRNA U36 is a member of the C/D box class of snoRNAs which contain the conserved sequence motifs known as the C box (UGAUGA) and the D box (CUGA). Most of the members of the box C/D family function in directing site-specific 2′-O-methylation of substrate RNAs. U36 is encoded within the intron of ribosomal protein rpL7a, and has two regions of complementarity to 18S and 28S ribosomal RNA. This complementarity suggests that U36 acts as a 2′-O-ribose methylation guide. This snoRNA is also related to other snoRNAs (snoR47 and Z100) identified in the rice plant Oryza sativa.

SURF4

Surfeit locus protein 4 or Surf4 is a protein involved in regulating export of some proteins from the endoplasmic reticulum to the golgi bodies. Surf4 is involved in trafficking soluble (i.e. non-membrane-bound) proteins, namely lipoproteins and PCSK9. It recognizes cargo proteins via a three-amino-acid sequence near the N-termini. The related protein in yeast is called Erv29p. This gene is named based on its location in the surfeit gene cluster, composed of six housekeeping genes that do not share sequence similarity. The encoded protein is a conserved integral membrane protein containing multiple putative transmembrane regions. Surf4’s yeast homolog is directly required for packaging glycosylated pro-alpha-factor into COPII vesicles. Eliminating Surf4 in the liver reduces the amount of lipid in the plasma and prevents atherosclerosis in mice.

  • Sun S, Tang X, Guo Y, Hu J (August 2021). “Endoplasmic reticulum composition and form: Proteins in and out”. Current Opinion in Cell Biology. 71: 1–6. doi:10.1016/j.ceb.2021.01.008. PMID 33611096. S2CID 231987943. “SURF4 Gene – Surfeit 4”. Retrieved 8 June 2022. “Entrez Gene: SURF4 surfeit 4”.

MED22 (REDIRECTED FROM SURF5)

Mediator of RNA polymerase II transcription subunit 22 is an enzyme that in humans is encoded by the MED22gene.

Yon J, Jones T, Garson K, Sheer D, Fried M (Mar 1993). “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. doi:10.1093/hmg/2.3.237. PMID 8499913.
Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC (Jun 2004). “A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology”. Molecular Cell. 14 (5): 685–91. doi:10.1016/j.molcel.2004.05.006. PMID 15175163.

Function

This gene is located in the surfeit gene cluster, a group of very tightly linked housekeeping genes that do not share sequence similarity. The gene is oriented in a head-to-head fashion with RPL7A (SURF3) and the two genes share a bidirectional promoter. The encoded proteins are localized to the cytoplasm. Two alternative transcript variants encoding different isoforms have been identified for this gene. “Entrez Gene: SURF5 surfeit 5”

Interactions

MED22 has been shown to interact with MED30.

Model organisms

Model organisms have been used in the study of MED22 function. A conditional knockout mouse line called Med22tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.  Additional screens performed: – In-depth immunological phenotyping.

  • Gerdin AK (2010). “The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice”. Acta Ophthalmologica. 88. doi:10.1111/j.1755-3768.2010.4142.x. S2CID 85911512. “International Mouse Phenotyping Consortium”.
  • Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). “A conditional knockout resource for the genome-wide study of mouse gene function”. Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  • Dolgin E (Jun 2011). “Mouse library set to be knockout”. Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718. Collins FS, Rossant J, Wurst W (Jan 2007). “A mouse for all reasons”. Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
  • White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (Jul 2013). “Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes”. Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131. “Infection and Immunity Immunophenotyping (3i) Consortium”.

SURF6

Surfeit locus protein 6 is a protein that in humans is encoded by the SURF6 gene.

This gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity. The gene demonstrates features of a housekeeping gene, being ubiquitously expressed, and the encoded protein has been localized to the nucleolus. The protein includes motifs found in both the mouse and fish orthologs, which suggests a putative function as a nucleolar-matrix protein with nucleic acid-binding properties, based on characteristics determined in mouse.

  • Duhig T, Ruhrberg C, Mor O, Fried M (May 1999). “The human Surfeit locus”. Genomics. 52 (1): 72–8. doi:10.1006/geno.1998.5372. PMID 9740673. “Entrez Gene: SURF6 surfeit 6”.

Further reading

SURF1

SURF3

SURF5

SURF6

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