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|Mutation Type||critical splice donor site|
|Coordinate||76,608,106 bp (GRCm38)|
|Base Change||C ⇒ T (forward strand)|
|Gene Name||collagen, type VI, alpha 2|
|Chromosomal Location||76,595,762-76,623,630 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for an ENU-induced allele exhibit reduced body weight. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000001181] [ENSMUSP00000101053]|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2017-01-06 10:53 AM by Anne Murray|
|Record Created||2016-04-20 8:13 PM|
The piddling phenotype was identified among N-nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R4242, some of which showed reduced body weights compared to wild-type littermates (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 34 mutations. The body weight phenotype was linked to a mutation in Col6a2: a G to A transition at base pair 76,608,106 (v38) on chromosome 10, or base pair 15,520 in the GenBank genomic region NC_000076 within the donor splice site of intron 16. Linkage was found with a recessive model of inheritance, wherein six variant homozygotes departed phenotypically from 19 homozygous reference mice and 24 heterozygous mice with a P value of 1.18 x 10-7 (Figure 2). A substantial semidominant effect was also observed (P = 5.528 x 10-6).
The effect of the mutation at the cDNA and protein level has not examined, but the mutation is predicted to result in the use of a cryptic splice site in intron 16. The resulting transcript would have a 57-base pair insertion in intron 16, resulting an in-frame insertion of 19 amino acids after amino acid 480 (in both COL6A2 protein variants). The protein would terminate at the appropriate site.
Genomic numbering corresponds to NC_000076. The donor splice site of intron 16, which is destroyed by the piddling mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
The Col6a2 gene encodes α2(VI), a 1,034 amino acid member of the type VI collagen family. In vertebrates, the collagen superfamily contains 28 different types of collagen (collagens I to XXVIII) (1;2). The type VI collagen family includes six highly homologous α-chains, α1-α6. Each of the collagen VI proteins has a large globular N-terminus that has multiple von Willebrand factor A-like (VWA) domains; α2(VI) has three VWA domains (Figure 3). The VWA domains putatively mediate the interaction between the collagens and other extracellular matrix proteins. The collagen VI proteins also have a 336 amino acid Gly-Xaa-Yaa repeat triple helix. The collagen VI proteins all have a Cys residue in the triple helical domain that stabilizes the assembly of higher-order structures (3;4). The triple helical domain of α2(VI) acts as a storage site for the preforms of collagenases, including proMMP-1, -3, and -8 (5); MMP-1, -3, and -13 activities are inhibited by α2(VI). At low concentrations, α2(VI) enhances the autolytic activation of proMMP-2 and substrate conversion rate of MMP-2, but reduces MMP-9 activation and activity; however, at high molar excesses, α2(VI) blocks the processing of proMMP-2.
Type VI collagen α-chains form α1α2α3 heterotrimers to make up single collagen molecules [(6-8); reviewed in (9). Alternative heterotrimers may also be formed comprised of a combination of α1, α2, and α5 or α6 (α1α2α5 or α1α2α6) (10). The α chains associate at their C-terminal globular domains, and hydrogen bonds link the three α-chains from the C-terminus to the N-terminus, leading to a triple-helical structure. The assembly of large collagen VI aggregates occurs before secretion. The association of the α1α2α3 (or α1α2α5 or α1α2α6) heterotrimers occurs before assembly of disulfide-bonded antiparallel dimers, which subsequently align to form tetramers that are also stabilized by disulfide bonds (3;7). The tetramers are secreted. In the extracellular space, the tetramers associate end-to-end to form beaded microfilaments (3;11-14). For more information about collagen folding and structure, please see the records for seal and aoba.
The piddling mutation is predicted to cause a 57-base pair insertion in intron 16, resulting an in-frame insertion of 19 amino acids after amino acid 480. The protein would terminate at the appropriate site. The 19-amino acid insertion would occur in the triple helical domain, possibly disrupting the assembly of higher order collagen VI structures.
Collagen VI is expressed in most connective tissues, including muscle, skin, tendon, cartilage, intervertebral discs, lens, internal organs, and blood vessels. Collagens are localized to the extracellular matrix.
Collagens form the structural basis of skin, tendon, bone, cartilage, and other tissues. Collagens are the most abundant proteins in the human body, making up approximately 30% of its protein mass (2). There are at least 28 collagen types and 42 α chains in vertebrates, in addition to a variety of proteins containing the collagen triple helix motif (2;15). Fibril-forming collagen orthologues have been identified in invertebrates (16), as well as in bacteria and viruses (17). Collagen VI has several functions, including mechanical functions, inhibition of apoptosis and oxidative damage, promotion of tumor growth and progression, regulation of cell differentiation, regulation of autophagy, maintenance of cell stemness, adhesion, proliferation, migration, cell survival, regulation and differentiation of adipocytes and of normal and malignant mammary ductal cells [reviewed in (18) and references therein]. Collagen VI α1, α2, and α3 chains are found in basement membrane structures in mouse skeletal muscles, and α1α2α3 heterotrimers are proposed to function in basement membrane integrity (19). In the ECM, collagen VI interacts with several proteins to anchor to the basement membrane, including collagen II, collagen IV (see the record for aoba), collagen XIV, fibulin 2, fibronectin, perlecan, microfibril-associated glycoprotein 1, membrane-associated chondroitin sulfate proteoglycan 4, biglycan, heparin, hyaluran, and decorin [reviewed in (9)]. Cell binding to collagen VI might be mediated by the membrane-associated chondroitin proteoglycan NG2 and integrins α1β1 and α2β1; integrins α5β1 and αVβ3 can also bind collagen VI [(20); reviewed in (9)].
A Col6a1 knockout (Col6a1-/-) mouse idoes not express collagen VI in muscle (21). The Col6a1-/- mice exhibit a mild neuromuscular disorder without much overt weakness (21). The muscles from the Col6a1-/- mice show increased apoptosis (22) and defective autophagocytic flux including mitochondrial autophagy (23) in muscle cells. Mutations in COL6A1, COL6A2, and COL6A3 are linked to two types of congenital muscular dystrophies: Bethlem myopathy 1 (BM1; OMIM: #158810) and Ullrich congenital muscular dystrophy 1 (UCMD1; OMIM: #254090) (24-30). Mutations in COL6A2 are also linked to congenital myosclerosis (OMIM: #255600), a recessive form of BM1 (31). BM1 and UCMD1 symptoms are usually evident at birth, with patients exhibiting hypotonia and weakness as well as hyperlaxity in the distal joints (32;33). The hands, fingers, and feet are extremely flexible and can bend backwards. Joint contractures have also been observed, affecting the elbows, knees, spine, and neck. In the neonatal period, some UCMD1 patients have transient feeding difficulties, which may lead to severe dysphagia (34). In severe cases of UCMD1, patients never gain the ability to walk, but the infants can usually learn to roll crawl, and sit (35). The muscle weakness phenotype is slowly progressive, but the resulting disability is aggravated by progressive contractures of the large joints (e.g., shoulder, elbows, hips, knees, and ankles). After the loss of ambulation, some patients exhibit respiratory insufficiency (e.g., nocturnal hypoxemia) (34). Patients with BM1 have variable phenotypes; the symptoms are typically milder than that in UCMD1. Infants with BM1 may exhibit hypotonia, foot deformities, and torticollis (i.e., wry neck or loxia) (36). The congenital contractures largely resolve in the first two years. Young children may exhibit mild weakness only, displaying distal joint hyperlaxity instead of contractures. Some patients with collagen VI-related myopathies exhibit skin phenotypes, including keratosis pilaris of the extensor surfaces of the arms and legs, abnormal scar formation, and/or a soft texture to the palmar skin of the hands and feet.
Body weight changes as the result of COL6A2 mutations have not been described. However, a Col6a3 mutant mouse model (Col6a3tm1Chu/Col6a3tm1Chu; MGI:5514357), which exhibits muscle and tendon defects, also had reduced body weight and organ weights (37). The weights of extensor digitorum longus, soleus, and tibialis anterior, gastrocnemius, quadriceps, and diaphragm muscles were reduced compared to that in wild-type mice. The body weight phenotype of the Col6a3tm1Chu/Col6a3tm1Chu mice progressed with age. Organ and muscle weights of the piddling mice were not examined, but the reduced overall body weights observed indicate that some α2(VI)piddling function is lost.
piddling(F):5'- TAACCTGCCATGGACTTGCC -3'
piddling(R):5'- TACAACAGAGTGGCCTCAGG -3'
piddling_seq(F):5'- CATGGACTTGCCTTGGCTG -3'
piddling_seq(R):5'- CTGAGGGGTTGAATAACTTATCCC -3'
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4. Chu, M. L., Conway, D., Pan, T. C., Baldwin, C., Mann, K., Deutzmann, R., and Timpl, R. (1988) Amino Acid Sequence of the Triple-Helical Domain of Human Collagen Type VI. J Biol Chem. 263, 18601-18606.
5. Freise, C., Erben, U., Muche, M., Farndale, R., Zeitz, M., Somasundaram, R., and Ruehl, M. (2009) The Alpha 2 Chain of Collagen Type VI Sequesters Latent Proforms of Matrix-Metalloproteinases and Modulates their Activation and Activity. Matrix Biol. 28, 480-489.
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7. Colombatti, A., Mucignat, M. T., and Bonaldo, P. (1995) Secretion and Matrix Assembly of Recombinant Type VI Collagen. J Biol Chem. 270, 13105-13111.
8. Chu, M. L., Pan, T. C., Conway, D., Saitta, B., Stokes, D., Kuo, H. J., Glanville, R. W., Timpl, R., Mann, K., and Deutzmann, R. (1990) The Structure of Type VI Collagen. Ann N Y Acad Sci. 580, 55-63.
9. Bonnemann, C. G. (2011) The Collagen VI-Related Myopathies: Muscle Meets its Matrix. Nat Rev Neurol. 7, 379-390.
10. Gara, S. K., Grumati, P., Urciuolo, A., Bonaldo, P., Kobbe, B., Koch, M., Paulsson, M., and Wagener, R. (2008) Three Novel Collagen VI Chains with High Homology to the alpha3 Chain. J Biol Chem. 283, 10658-10670.
11. Knupp, C., Pinali, C., Munro, P. M., Gruber, H. E., Sherratt, M. J., Baldock, C., and Squire, J. M. (2006) Structural Correlation between Collagen VI Microfibrils and Collagen VI Banded Aggregates. J Struct Biol. 154, 312-326.
12. Bernardi, P., and Bonaldo, P. (2008) Dysfunction of Mitochondria and Sarcoplasmic Reticulum in the Pathogenesis of Collagen VI Muscular Dystrophies. Ann N Y Acad Sci. 1147, 303-311.
13. Engvall, E., Hessle, H., and Klier, G. (1986) Molecular Assembly, Secretion, and Matrix Deposition of Type VI Collagen. J Cell Biol. 102, 703-710.
14. Baldock, C., Sherratt, M. J., Shuttleworth, C. A., and Kielty, C. M. (2003) The Supramolecular Organization of Collagen VI Microfibrils. J Mol Biol. 330, 297-307.
15. Brodsky, B., and Persikov, A. V. (2005) Molecular Structure of the Collagen Triple Helix. Adv Protein Chem. 70, 301-339.
16. Exposito, J. Y., Cluzel, C., Garrone, R., and Lethias, C. (2002) Evolution of Collagens. Anat Rec. 268, 302-316.
17. Rasmussen, M., Jacobsson, M., and Bjorck, L. (2003) Genome-Based Identification and Analysis of Collagen-Related Structural Motifs in Bacterial and Viral Proteins. J Biol Chem. 278, 32313-32316.
18. Cescon, M., Gattazzo, F., Chen, P., and Bonaldo, P. (2015) Collagen VI at a Glance. J Cell Sci. 128, 3525-3531.
19. Sabatelli, P., Gualandi, F., Gara, S. K., Grumati, P., Zamparelli, A., Martoni, E., Pellegrini, C., Merlini, L., Ferlini, A., Bonaldo, P., Maraldi, N. M., Paulsson, M., Squarzoni, S., and Wagener, R. (2012) Expression of Collagen VI alpha5 and alpha6 Chains in Human Muscle and in Duchenne Muscular Dystrophy-Related Muscle Fibrosis. Matrix Biol. 31, 187-196.
20. Kuo, H. J., Maslen, C. L., Keene, D. R., and Glanville, R. W. (1997) Type VI Collagen Anchors Endothelial Basement Membranes by Interacting with Type IV Collagen. J Biol Chem. 272, 26522-26529.
21. Bonaldo, P., Braghetta, P., Zanetti, M., Piccolo, S., Volpin, D., and Bressan, G. M. (1998) Collagen VI Deficiency Induces Early Onset Myopathy in the Mouse: An Animal Model for Bethlem Myopathy. Hum Mol Genet. 7, 2135-2140.
22. Irwin, W. A., Bergamin, N., Sabatelli, P., Reggiani, C., Megighian, A., Merlini, L., Braghetta, P., Columbaro, M., Volpin, D., Bressan, G. M., Bernardi, P., and Bonaldo, P. (2003) Mitochondrial Dysfunction and Apoptosis in Myopathic Mice with Collagen VI Deficiency. Nat Genet. 35, 367-371.
23. Grumati, P., Coletto, L., Sabatelli, P., Cescon, M., Angelin, A., Bertaggia, E., Blaauw, B., Urciuolo, A., Tiepolo, T., Merlini, L., Maraldi, N. M., Bernardi, P., Sandri, M., and Bonaldo, P. (2010) Autophagy is Defective in Collagen VI Muscular Dystrophies, and its Reactivation Rescues Myofiber Degeneration. Nat Med. 16, 1313-1320.
24. Demir, E., Sabatelli, P., Allamand, V., Ferreiro, A., Moghadaszadeh, B., Makrelouf, M., Topaloglu, H., Echenne, B., Merlini, L., and Guicheney, P. (2002) Mutations in COL6A3 Cause Severe and Mild Phenotypes of Ullrich Congenital Muscular Dystrophy. Am J Hum Genet. 70, 1446-1458.
25. Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., and Pepe, G. (2005) Dominant and Recessive COL6A1 Mutations in Ullrich Scleroatonic Muscular Dystrophy. Ann Neurol. 58, 400-410.
26. Lucarini, L., Giusti, B., Zhang, R. Z., Pan, T. C., Jimenez-Mallebrera, C., Mercuri, E., Muntoni, F., Pepe, G., and Chu, M. L. (2005) A Homozygous COL6A2 Intron Mutation Causes in-Frame Triple-Helical Deletion and Nonsense-Mediated mRNA Decay in a Patient with Ullrich Congenital Muscular Dystrophy. Hum Genet. 117, 460-466.
27. Lucioli, S., Giusti, B., Mercuri, E., Vanegas, O. C., Lucarini, L., Pietroni, V., Urtizberea, A., Ben Yaou, R., de Visser, M., van der Kooi, A. J., Bonnemann, C., Iannaccone, S. T., Merlini, L., Bushby, K., Muntoni, F., Bertini, E., Chu, M. L., and Pepe, G. (2005) Detection of Common and Private Mutations in the COL6A1 Gene of Patients with Bethlem Myopathy. Neurology. 64, 1931-1937.
28. Baker, N. L., Morgelin, M., Peat, R., Goemans, N., North, K. N., Bateman, J. F., and Lamande, S. R. (2005) Dominant Collagen VI Mutations are a Common Cause of Ullrich Congenital Muscular Dystrophy. Hum Mol Genet. 14, 279-293.
29. Baker, N. L., Morgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F., and Lamande, S. R. (2007) Molecular Consequences of Dominant Bethlem Myopathy Collagen VI Mutations. Ann Neurol. 62, 390-405.
30. Higuchi, I., Shiraishi, T., Hashiguchi, T., Suehara, M., Niiyama, T., Nakagawa, M., Arimura, K., Maruyama, I., and Osame, M. (2001) Frameshift Mutation in the Collagen VI Gene Causes Ullrich's Disease. Ann Neurol. 50, 261-265.
31. Merlini, L., Martoni, E., Grumati, P., Sabatelli, P., Squarzoni, S., Urciuolo, A., Ferlini, A., Gualandi, F., and Bonaldo, P. (2008) Autosomal Recessive Myosclerosis Myopathy is a Collagen VI Disorder. Neurology. 71, 1245-1253.
32. Bertini, E., and Pepe, G. (2002) Collagen Type VI and Related Disorders: Bethlem Myopathy and Ullrich Scleroatonic Muscular Dystrophy. Eur J Paediatr Neurol. 6, 193-198.
33. Lampe, A. K., and Bushby, K. M. (2005) Collagen VI Related Muscle Disorders. J Med Genet. 42, 673-685.
34. Nadeau, A., Kinali, M., Main, M., Jimenez-Mallebrera, C., Aloysius, A., Clement, E., North, B., Manzur, A. Y., Robb, S. A., Mercuri, E., and Muntoni, F. (2009) Natural History of Ullrich Congenital Muscular Dystrophy. Neurology. 73, 25-31.
35. Brinas, L., Richard, P., Quijano-Roy, S., Gartioux, C., Ledeuil, C., Lacene, E., Makri, S., Ferreiro, A., Maugenre, S., Topaloglu, H., Haliloglu, G., Penisson-Besnier, I., Jeannet, P. Y., Merlini, L., Navarro, C., Toutain, A., Chaigne, D., Desguerre, I., de Die-Smulders, C., Dunand, M., Echenne, B., Eymard, B., Kuntzer, T., Maincent, K., Mayer, M., Plessis, G., Rivier, F., Roelens, F., Stojkovic, T., Taratuto, A. L., Lubieniecki, F., Monges, S., Tranchant, C., Viollet, L., Romero, N. B., Estournet, B., Guicheney, P., and Allamand, V. (2010) Early Onset Collagen VI Myopathies: Genetic and Clinical Correlations. Ann Neurol. 68, 511-520.
36. Jobsis, G. J., Boers, J. M., Barth, P. G., and de Visser, M. (1999) Bethlem Myopathy: A Slowly Progressive Congenital Muscular Dystrophy with Contractures. Brain. 122 ( Pt 4), 649-655.
37. Pan, T. C., Zhang, R. Z., Markova, D., Arita, M., Zhang, Y., Bogdanovich, S., Khurana, T. S., Bonnemann, C. G., Birk, D. E., and Chu, M. L. (2013) COL6A3 Protein Deficiency in Mice Leads to Muscle and Tendon Defects Similar to Human Collagen VI Congenital Muscular Dystrophy. J Biol Chem. 288, 14320-14331.
|Science Writers||Anne Murray|
|Authors||Emre Turer and Bruce Beutler|
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