Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia

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.

Collagen 11a1 is indirectly activated by lymphocyte enhancer-binding factor 1 (Lef1) and negatively regulates osteoblast maturation

“…Further evidence for this conclusion is apparent in the Cho mice, which exhibit excess mineralization in the long bones (Seegmiller et al, 1971;Li et al, 1995). Sequence variations in the Col11a1 gene are also associated with osteoarthritis, early-onset osteoarthritis, degenerative lumbar spinal stenosis and cleft palate (Melkoniemi et al, 2003;Noponen-Hietala et al, 2003;Rodriguez et al, 2004;Jakkula et al, 2005). Its association with a variety of common diseases makes Col11a1 an important target for musculoskeletal disease research.…”

Multiple functions of Snail family genes during palate development in mice

“…Most newborns with Pierre Robin Sequence also exhibit respiratory and feeding difficulties. Cases of Pierre Robin Sequence are both phenotypically and genetically heterogeneous (Cohen, 1999;Houdayer et al, 2001;Jakobsen et al, 2006;Jamshidi et al, 2004;Melkoniemi et al, 2003;Ounap et al, 2005;Ricks et al, 2002). Pierre Robin Sequence can occur as an isolated nonsyndromic form, or can occur in combination with other syndromes.…”

“…Pierre Robin Sequence can occur as an isolated nonsyndromic form, or can occur in combination with other syndromes. Mutations in several collagen genes, including COL2A1, COL11A1 and COL11A2, have been found in subjects with nonsyndromic Pierre Robin Sequence (Melkoniemi et al, 2003), although it has not been established definitively that these mutations are causal for the observed malformations. In addition, chromosomal translocations (Jamshidi et al, 2004), duplications (Ounap et al, 2005) and deletions (Houdayer et al, 2001) have been described that are associated with nonsyndromic Pierre Robin Sequence.…”

“…Cases of Pierre Robin Sequence are both phenotypically and genetically heterogeneous (Cohen, 1999;Houdayer et al, 2001;Jakobsen et al, 2006;Jamshidi et al, 2004;Melkoniemi et al, 2003;Ounap et al, 2005;Ricks et al, 2002). The association of mandibular defects with palatal clefting has been observed in several mouse models of cleft palate, including Hoxa2 (Gendron-Maguire et al, 1993), Egfr (Miettinen et al, 1999) and Dmm (disproportionate micromelia, a dominant mutant allele of the Col2a1 gene) (Ricks et al, 2002) mutant mice.…”

Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence

“…In humans, cleft palate due to mechanical interference with palatal shelf elevation by a malpositioned tongue and small jaw is clinically classified as Pierre Robin sequence or syndrome (PRS) (Rangeeth et al, 2011). Studies of human patients have shown that mutations in SATB2, SOX9, BMP2 and the collagens lead to PRS-like clefting (Melkoniemi et al, 2003;Tan et al, 2013). The etiology of PRS has also been associated with a range of syndromes and chromosomal anomalies plus extrinsic fetal deformational forces, but the developmental mechanisms causing this condition are unclear, in part because of the lack of an animal model (Tan et al, 2013).…”