COL11A2 – Stickler Syndrome

COL11A2 encodes the alpha-2 chain of type XI collagen and is implicated in non-ocular Stickler syndrome (MONDO:0019354), also known as type III Stickler syndrome. This autosomal dominant connective tissue disorder is characterised by hearing impairment, midfacial hypoplasia, cleft palate, early-onset osteoarthritis, and skeletal dysplasia with or without ocular findings. COL11A2 mutations were first linked to a family with Stickler syndrome lacking eye involvement, defining a distinct clinical subtype (PMID:9506662; PMID:7833911).

Genetic evidence supports a dominant inheritance mode for COL11A2-related Stickler syndrome, with heterozygous in-frame and truncating variants segregating with disease in multiple multi-generation pedigrees. A 27-bp in-frame deletion in exon 57 was identified in two unrelated families with non-ocular Stickler syndrome (PMID:9506662). Linkage analysis in a large Dutch kindred provided a LOD score of 4.36 near COL11A2, confirming its role in ocular-sparing Stickler syndrome (PMID:7833911).

Although most COL11A2 mutations act dominantly, autosomal recessive presentations occur in otospondylomegaepiphyseal dysplasia (OSMED), a Stickler-related variant. Compound heterozygous splice–site mutations (c.3774C>T and c.4750+5>A) have been reported to cause OSMED with progressive deafness, spondyloepiphyseal dysplasia, platyspondyly (HP:0000926), and early osteoarthritis (HP:0002758) in a 29-year-old male patient (PMID:37347055).

The COL11A2 variant spectrum encompasses missense, nonsense, frameshift, in-frame deletions, and canonical splice–site changes. A representative missense change, c.2678C>T (p.Pro893Leu), segregates with non-ocular Stickler syndrome in a heterozygous state and induces exon skipping in vitro (PMID:15372529). Intronic variant c.4392+1G>A disrupts normal splicing, leading to in-frame deletions within the triple helical domain (PMID:33348901).

Functional assays demonstrate that deleterious COL11A2 transcripts yield aberrant collagen XI α2 chains, impair fibrillogenesis, and produce a dominant-negative effect on collagen assembly. Exon-trapping studies confirmed abnormal exon skipping for c.4392+1G>A, resulting in shorter α2 chains lacking critical Gly-X-Y repeats (PMID:33348901). Zebrafish col11a2 knockout models develop vertebral fusions analogous to human skeletal defects, and patient-derived missense transgenes fail to rescue these phenotypes, corroborating a loss-of-function mechanism (PMID:37462524).

Collectively, the convergent genetic and experimental data establish a strong gene–disease relationship between COL11A2 and Stickler syndrome. Targeted sequencing of COL11A2 is essential for diagnosis, especially in patients with hearing loss (HP:0000365), cleft palate (HP:0000175), osteoarthritis (HP:0002758), and platyspondyly (HP:0000926) absent classical ocular anomalies. Key take-home: COL11A2 mutation screening refines diagnosis and informs genetic counselling for non-ocular and atypical Stickler syndrome presentations.

References

• The Journal of Pediatrics • 1998 • Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha2(XI) chain of type XI collagen PMID:9506662
• Human Molecular Genetics • 1994 • A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene PMID:7833911
• American Journal of Medical Genetics Part A • 2004 • A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome PMID:15372529
• Genes • 2020 • Exon-Trapping Assay Improves Clinical Interpretation of COL11A1 and COL11A2 Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia PMID:33348901
• Frontiers in Genetics • 2023 • Case report: Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2 PMID:37347055
• Human Molecular Genetics • 2023 • COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis PMID:37462524

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