Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss.
BACKGROUND
Stickler syndromes types 1, 2 and 3 are usually dominant disorders caused by mutations in the genes COL2A1, COL11A1 and COL11A2 that encode the fibrillar collagens types II and XI present in cartilage and vitreous. Rare recessive forms of Stickler syndrome exist that are due to mutations in genes encoding type IX collagen (COL9A1 type 4 Stickler syndrome and COL9A2 type 5 Stickler syndrome). Recently, recessive mutations in the COL11A1 gene have been demonstrated to result in fibrochondrogenesis, a much more severe skeletal dysplasia, which is often lethal. Here we demonstrate that some mutations in COL11A1 are recessive, modified by alternative splicing and result in type 2 Stickler syndrome rather than fibrochondrogenesis.


METHODS
Patients referred to the national Stickler syndrome diagnostic service for England, UK were assessed clinically and subsequently sequenced for mutations in COL11A1. Additional in silico and functional studies to assess the effect of sequence variants on pre-mRNA processing and collagen structure were performed.


RESULTS
In three different families, heterozygous COL11A1 biallelic null, null/missense or silent/missense mutations, were found. They resulted in a recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss and are clinically distinct from the recessive types 4 and 5 variants of Stickler syndrome. One mutant allele in each family is capable of synthesising a normal α1(XI) procollagen molecule, via variable pre-mRNA processing.


CONCLUSIONS
This new variant has important implications for molecular diagnosis and counselling families with type 2 Stickler syndrome.
Department of Pathology, University of Cambridge, Cambridge, UK.
Allan J
AJ
Richards
Gregory S
GS
Fincham
Annie
A
McNinch
David
D
Hill
Arabella V
AV
Poulson
Bruce
B
Castle
Melissa M
MM
Lees
Anthony T
AT
Moore
John D
JD
Scott
Martin P
MP
Snead
D000328:Adult; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D002675:Child, Preschool; D024161:Collagen Type XI / Q000172:deficiency / Q000235:genetics*; D003240:Connective Tissue Diseases / Q000235:genetics*; D005260:Female; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020255:Vitreous Detachment / Q000235:genetics*
C574182:COL11A1 protein, human; D024161:Collagen Type XI
Alternative Splicing; Recessive Inheritance; Stickler syndrome