Abstract
Cleft palate is a common birth defect, but its etiopathogenesis is mostly unknown. Several studies have shown that cleft palate has a strong genetic component. Robin sequence consists of three of the following four findings: micrognathia, glossoptosis, obstructive apnea, and cleft palate. While cleft palate is mainly nonsyndromic, about 80 percent of Robin sequence cases are associated with syndromes. Mutations in genes coding for cartilage collagens II and XI, COL2A1, COL11A1 and COL11A2, have been shown to cause chondrodysplasias that are commonly associated with Robin sequence, micrognathia or cleft palate. We therefore analyzed a cohort of 24 patients with nonsyndromic Robin sequence, 17 with nonsyndromic cleft palate and 21 with nonsyndromic micrognathia for mutations in COL11A2. A total of 23 Robin sequence patients were also analyzed for mutations in COL2A1 and COL11A1. We detected two disease-associated mutations in patients with Robin sequence, an Arg to stop codon mutation in COL11A2 and a splicing mutation in COL11A1. Two putatively disease-associated sequence variations were found in COL11A1 in Robin sequence patients, one in COL11A2 in a patient with micrognathia and one in COL2A1 in two patients with Robin sequence. The results showed that sequence variations in these genes can play a role in the etiology of Robin sequence, cleft palate and micrognathia but are not common causes of these phenotypes.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Schutte BC, Murray JC: The many faces and factors of orofacial clefts. Hum Mol Genet 1999; 8: 1853–1859.
Murray JC: Face facts: genes, environment and clefts. Am J Hum Genet 1995; 57: 227–232.
Robin P: La chute de la base de la langue considerée comme une nouvelle cause de gêne dans la respiration naso-pharyngienne. Bull Acad Natl Med(Paris) 1923; 89: 37–41.
Shprintzen RJ: The implications of the diagnosis of Robin sequence. Cleft Palate Craniofac J 1992; 29: 205–209.
Marques IL, Barbieri MA, Bettiol H: Etiopathogenesis of isolated Robin sequence. Cleft Palate Craniofac J 1998; 35: 517–525.
Prescott NJ, Lees MM, Winter RM, Malcolm S: Identification of susceptibility for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sibpairs. Hum Genet 2000; 106: 345–350.
Sakata Y, Tokunaga K, Yonehara Y et al: Significant association of HLA-B and HLA-DRB1 alleles with cleft lip with or without cleft palate. Tissue Antigens 1999; 53: 147–152.
Wong FK, Hagberg C, Karsten A et al: Linkage analysis of candidate regions in Swedish nonsyndromic cleft lip with or without cleft palate families. Cleft Palate Craniofac J 2000; 37: 357–362.
Annunen S, Körkkö J, Czarny M et al: Splicing mutations of 54 bp exons in the COL11A1 gene cause Marshall syndrome but other mutations cause overlapping Marshall/Stickler phenotypes. Am J Hum Genet 1999; 65: 974–983.
Vuoristo MM, Pihlajamaa T, Vanderberg P, Prockop DJ, Ala-Kokko L: The human COL11A2 gene structure indicates that the gene has not evolved with the genes for the major fibrillar collagens. J Biol Chem 1995; 270: 22873–22881.
Ala-Kokko L, Kvist A-P, Metsäranta M et al: Conservation of the sizes of 53 introns and over 100 intronic sequences for the binding of common transcription factors in the human and mouse genes for type II procollagen (COL2A1). Biochem J 1995; 308: 923–929.
Eyre D, Wu JJ: Type XI or 1α2α3α collagen; in Mayne R, Burgeson RE, (eds): Structure and function of collagen types. Academic Press, New York: 1987, pp 261–281.
Chung KS, Park HH, Ting K et al: Modulated expression of type X collagen in the Meckel's cartilage with different developmental fates. Dev Biol 1995; 170: 387–396.
Spranger J: The type XI collagenopathies. Pediatr Radiol 1998; 28: 745–750.
Sirko-Osadsa DA, Murray MA, Scott JA, Lavery MA, Warman ML, Robin NH: Stickler syndrome without eye involvement is caused by mutations in COL11A2 the gene encoding the α2(XI) chain of type XI collagen. J Pediatr 1998; 132: 368–371.
Melkoniemi M, Brunner HG, Manouvrier S et al: Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. Am J Hum Genet 2000; 66: 368–377.
Pihlajamaa T, Prockop DJ, Faber J et al: Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher–Zweymüller syndrome with heterozygous OSMED (nonocular Stickler syndrome). Am J Med Genet 1998; 80: 115–120.
Myllyharju J, Kivirikko KI: Collagens and collagen-related diseases. Ann Med 2001; 33: 7–21.
Broadbent BH, Broadbent Jr BH, Golden WH: Bolton standards of dentofacial developmental growth. Saint Louis: CV Mosby Co., 1975.
Körkkö J, Annunen S, Pihlajamaa T, Prockop DJ, Ala-Kokko L: Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: comparison with denaturing gradient gel electrophoresis and nucleotide sequencing. Proc Natl Acad Sci USA 1998; 95: 1681–1685.
Ala-Kokko L: Genetic risk factors for lumbar disc disease. Ann Med 2002; 34: 42–47.
Cartegni J, Chew SL, Krainer AR: Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 2002; 3: 285–298.
Zeniou M, Pannetier S, Fryns JP, Hanauer A: Unusual splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin–Lowry syndrome. Am J Hum Genet 2002; 70: 1421–1433.
Vanderberg P, Vuoristo MM, Ala-Kokko L, Prockop DJ: The mouse col11a2 gene. Some transcripts from the adjacent rxr-β gene extend into the col11a2 gene. Matrix Biol 1996; 15: 359–367.
Benke PJ: The isotretionin teratogen syndrome. JAMA 1984; 251: 3267–3269.
Lammer EJ, Chen DT, Hoar RM et al: Retinoic acid embryopathy. N Eng J Med 1995; 313: 837–841.
McGuirt WT, Prasad SD, Griffith AJ et al: Mutations in COL11A2 cause nonsyndromic hearing loss (DFNA13). Nat Genet 1999; 23: 413–419.
Körkkö J, Kuivaniemi H, Paassilta P et al: Two new recurrent nucleotide mutations in the COL1A1 gene in four patients with osteogenesis imperfecta: about one-fifth are recurrent. Hum Mut 1997; 9: 148–156.
Fraser FC: The genetics of cleft lip and cleft palate. Am J Hum Genet 1970; 22: 336–352.
Acknowledgements
We thank all the patients and their families who participated in this study, and also Mrs Aira Harju and Ms Minta Lumme for their expert technical assistance. This work was partially supported by the Academy of Finland (grants to LA-K and JK), the Arthritis Foundation, the European Commission Grant (QLRT2001-02188), the Louisiana Gene Therapy Research Consortium (New Orleans, LA) and HCA-The Healthcare Company (Memphis, TN) (to LA-K), the Helsinki University Hospital Research Funds, the Sigrid Juselius Foundation (to JK) and NIH grant HD22657 (to DC and DK).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Melkoniemi, M., Koillinen, H., Männikkö, M. et al. Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia. Eur J Hum Genet 11, 265–270 (2003). https://doi.org/10.1038/sj.ejhg.5200950
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5200950
Keywords
This article is cited by
-
Best practice guidelines in managing the craniofacial aspects of skeletal dysplasia
Orphanet Journal of Rare Diseases (2021)
-
Transcriptional analysis of cleft palate in TGFβ3 mutant mice
Scientific Reports (2020)
-
Conditional deletion of Bmp2 in cranial neural crest cells recapitulates Pierre Robin sequence in mice
Cell and Tissue Research (2019)
-
Distinct DNA methylation profiles in subtypes of orofacial cleft
Clinical Epigenetics (2017)
-
Discovery of candidate genes for nonsyndromic cleft lip palate through genome-wide linkage analysis of large extended families in the Malay population
BMC Genetics (2016)
