RESEARCH ARTICLE

A Loss of Function Mutation in the COL9A2 GeneCause Autosomal Recessive Stickler SyndromeStuart Baker,1 Carol Booth,2 Corrine Fillman,1 Michael Shapiro,3 Michael P. Blair,3 James C. Hyland,1

and Leena Ala-Kokko1*1Connective Tissue Gene Tests, Allentown, Pennsylvania2Department of Pediatrics, Advocate Lutheran General Children’s Hospital, Illinois3Retina Consultants Ltd., Des Plaines, Illinois

Received 18 January 2011; Accepted 31 March 2011

Stickler syndrome is characterized by ocular, auditory, skeletal,

and orofacial abnormalities. We describe a family with autoso-

mal recessive Stickler syndrome. The main clinical findings

consisted of high myopia, vitreoretinal degeneration, retinal

detachment, hearing loss, and short stature. Affected family

members were found to have a homozygous loss-of-function

mutation in COL9A2, c.843_c.846þ 4del8. A family with auto-

somal recessive Stickler syndrome was previously described and

found to have a homozygous loss-of-function mutation in

COL9A1. COL9A1, COL9A2, and COL9A3 code for collagen IX.

All three collagen IX a chains, a1, a2, and a3, are needed for

formation of functional collagen IX molecule. In dogs, two

causative loci have been identified in autosomal recessive ocu-

loskeletal dysplasia. This dysplasia resembles Stickler syndrome.

Recently, homozygous loss-of-function mutations in COL9A2

and COL9A3 were found to co-segregate with the loci. Together

the data from the present study and the previous studies suggest

that loss-of-function mutations in any of the collagen IX genes

can cause autosomal recessive Stickler syndrome.

� 2011 Wiley-Liss, Inc.

Key words: cartilage; collagen; COL9A2; mutation; Stickler

syndrome

INTRODUCTION

Stickler syndrome, arthro-ophthalmopathy, is a clinically variable

and genetically heterogenous disorder [Stickler et al., 1965; Fran-

comano et al., 1987; Robin et al., 2000]. Its incidence among

neonates is estimated to be approximately 1 in 7,500 to 1 in

9,000. Stickler syndrome has been described with both autosomal

dominant and autosomal recessive inheritance with dominant

forms responsible for most cases. Autosomal dominant Stickler

syndrome includes Stickler syndrome type I (STL1, MIM 108300),

Stickler syndrome type II (STL2, MIM 604841), and Stickler

syndrome type III (STL3, MIM 184840). STL1 and STL2 are

characterized by the eye findings of high myopia, vitreoretinal

degeneration, retinal detachment, and cataracts. Additional find-

ingsmay includemidline clefting (cleft palate or bifid uvula), Pierre

Robin sequence, flat midface, sensorineural or conductive hearing

loss, mild spondyloepiphyseal dysplasia, and early-onset osteoar-

thritis. STL1 is caused by mutations in the COL2A1 gene (MIM

120140) [Ahmad et al., 1991; Hoornaert et al., 2010; Richards et al.,

2010] and STL2 is caused bymutations in theCOL11A1 gene (MIM

120280) [Richards et al., 1996; Annunen et al., 1999; Majava et al.,

2007]. The clinical findings of STL3 are similar to those of STL1 and

STL2 except for the lack of ocular findings in STL3. STL3 is caused

by mutations in the COL11A2 gene (MIM 120290) [Sirko-Osadsa

et al., 1998; Vuoristo et al., 2001]. STL3 is not associated with eye

findings becauseCOL11A2 is not expressed in the eye. It is replaced

by COL5A2 (MIM 120190) in this organ.

Marshall syndrome shares many manifestations in common

with STL1 and STL2 [Shanske et al., 1997; Griffith et al., 1998;

Annunen et al., 1999; Majava et al., 2007]. Additional findings may

include short stature and more pronounced facial changes con-

sisting of markedly short and flat nose with anteverted nostrils.

Marshall syndrome is allelic to STL2 [Griffith et al., 1998; Annunen

et al., 1999; Majava et al., 2007].

Recently, a family with autosomal recessive Stickler syndrome

was reported byVanCamp et al. [2006]. Affected individuals in this

familywere reported tohave clinical findings similar to STL1, STL2,

and Marshall syndrome. The major findings include moderate to

*Correspondence to:

Leena Ala-Kokko, Connective Tissue Gene Tests, 6580 Snowdrift Road,

Suite 300, Allentown, PA 18106. E-mail: leena.ala-kokko@ctgt.net

Published online 10 June 2011 in Wiley Online Library

(wileyonlinelibrary.com).

DOI 10.1002/ajmg.a.34071

How to Cite this Article:Baker S, Booth C, Fillman C, ShapiroM, Blair

MP, Hyland JC, Ala-Kokko L. 2011. A loss of

functionmutation in theCOL9A2 gene causes

autosomal recessive Stickler syndrome.

Am J Med Genet Part A 155:1668–1672.

� 2011 Wiley-Liss, Inc. 1668

high myopia, vitreoretinal degeneration, moderate to severe sen-

sorineural hearing loss, and epiphyseal dysplasia. The family re-

ported in this study was found to have a homozygous mutation,

Arg295Ter, in the COL9A1 gene.

The COL2A1, COL11A1, and COL11A2 genes code for collagen

a1(II),a1(XI), anda2(XI) chains [Myllyharju andKivirikko, 2001;

Eyre, 2002; Reginato and Olsen, 2002; Carter and Raggio, 2009].

Collagen II is a homotrimer of three identical a1(II) chains.

Collagen XI is a heterotrimer of three dissimilar a chains: a1(XI),a2(XI), and a3(XI). The a3(XI) chain is encoded by the COL2A1

gene. Collagen IX is a heterotrimer consisting of three genetically

different a chains: a1(IX), a2(IX), and a3(IX) encoded by the

COL9A1 (MIM 120210), COL9A2 (MIM 120260), and COL9A3

(MIM 120270) genes.

Collagens II, IX, and XI are structurally and functionally related

to each other [Myllyharju andKivirikko, 2001; Eyre, 2002; Reginato

and Olsen, 2002; Carter and Raggio, 2009]. Collagens II and XI are

fibrillar collagens and collagen IX is a fibril-associated collagenwith

interrupted triple helices. Collagen IX consists of three collagenous

domains, COL1–COL3, flanked by four non-collagenous domains,

NC1–NC4. Collagens II, IX, and XI are in general expressed in the

same tissues including hyaline cartilage, the vitreous of the eye,

intervertebral disc, and inner ear where they form a heteropoly-

meric fibril.

We describe a family of Asian Indian origin with characteristics

of autosomal recessive Stickler syndrome.

METHODS

The family with Stickler syndrome came to our attention when the

proposita (V-2; Fig. 1) was referred by a retinal specialist to confirm

the diagnosis of Stickler syndrome prior to having preventive laser

surgery to reduce her risk of retinal detachment. She is a 9-year-old

girl with severe myopia, vitreous abnormalities, and severe lattice

degeneration. She is the second child of unaffected consanguineous

parents (first cousins). She was born at term and weighed 2,410 g

and therewerenoearlyhealthproblems.At the ageof 2years shewas

diagnosedwithhighmyopia andprescribedglasses.At the ageof six,

prior to the family’s emigration to the United States, the child had

one eye treated with cryotherapy for retinal changes. Following

emigration to the United States, the girl’s speech was unusual

requiring speech therapy. Although she passed her initial hearing

screen at school, she was eventually retested and found to havemild

tomoderate sensorineural hearing loss. Her hearing aids have been

well tolerated. The proposita continues to have difficulties produc-

ing high-frequency sounds but there are no knownabnormalities of

her soft palate. She is well below the third centile for height. Her

upper to lower segment ratio is normal for age. Her facial profile is

flat and she has been diagnosed with flat feet. There are no other

orthopedic problems noted at this time and she has excellent

cognitive skills and no learning disabilities. A full skeletal survey

did not show any abnormalities.

The couple’s third child (V-3; Fig. 1) was born at term weighing

3,373 g. He is currently 18 months old and is well below the third

centile for height and weight. He failed his newborn hearing screen

and has mild to moderate sensorineural hearing loss. He has also

been diagnosedwith highmyopia. He has a flatmidface and a small

mandible. He has a normal palate and his speech is appropriate for

age. He has no orthopedic problems.

Both parents have normal vision and hearing. The father (IV-3;

Fig. 1) is 163 cm tall and the mother (IV-4; Fig. 1) is 160 cm in

height. Neither parent reports medical or orthopedic problems.

The paternal andmaternal grandmothers (III-2 and III-3; Fig. 1)

are sisters. They are two of eight children born to consanguineous

parents living in India. Three of the eight sibs have severe vision loss

and hearing problems which started in childhood (III-8, III-9, and

III-10; Fig. 1). Two of the affected sibs have experienced retinal

detachments and are now blind. The third sib is currently under-

goingpreventive treatment.All havenormal intelligence.The great-

uncle of the proposita (II-3) also married a first-cousin and has

FIG. 1. Pedigree of family with autosomal recessive Stickler syndrome. Filled symbols indicate clinically affected individuals; open symbols indicate

unaffected individuals; squares indicate males; circles indicate females; triangles with a slash indicate a terminated pregnancy; triangles without a

slash indicate miscarriage; partners with two relationship lines indicate consanguinity; the proposita is marked with an arrow.

BAKER ET AL. 1669

three children with vision and hearing loss (III-11, III-12, and III-

13; Fig. 1).

No member of the family is known to have a cleft palate and

overall the adult height is thought to be appropriate for this family.

One affected family member has difficulties moving around, which

is possibly associated with joint pain.

The pattern of inheritance in this family was highly suggestive of

autosomal recessive inheritance because of multiple affected chil-

dren being born to unaffected but consanguineous parents in

several generations. Since Van Camp et al. [2006] described a

family with autosomal recessive Stickler syndrome and a homozy-

gous loss-of-functionCOL9A1mutation and since it is known that

the assembly of functional collagen IX molecules requires the

presence of all three a(IX) chains, we adopted a candidate gene

approach focused on all three collagen IX genes [Hagg et al., 1997;

Pihlajamaa et al., 1998]. Sequence analysis of selected COL9A1,

COL9A2, and COL9A3 exons and exon boundaries was performed

on genomic DNA derived from the proposita (V-2; Fig. 1)

[Pihlajamaa et al., 1998; Paassilta et al., 1999b].

RESULTS

DNA sequencing demonstrated a heterozygous neutral change,

c.129C>T (rs2273079), in exon 2 of the COL9A3 gene. Since the

pedigree analysis suggested a homozygous pathogenic mutation,

COL9A3 was excluded. Because the initial screen of COL9A1 and

COL9A2 genes did not show any heterozygous variants, the re-

maining exons were analyzed. This resulted in identification of a

homozygous c.843_c.846þ 4del8 in the COL9A2 gene. This dele-

tion includes the last four nucleotides (CGAG) in exon 16 and the

first four nucleotides (GTGA) in the IVS16 sequence (Fig. 2). The

nucleotide sequence preceding the deletion in exon 16 (GTGA)

corresponds exactly to the first four nucleotides in the IVS16

sequence which were deleted (Fig. 2). Thus, it is possible that the

mutation arose by slipped-strand misparing [Levinson and

Gutman, 1987]. It is likely that the deletion does not affect the

donor splice site and instead results in a frameshift anddownstream

premature termination codon, Asp281GlnfsX70. The remaining

family members were analyzed for the COL9A2 exon 16 deletion

(IV-3, IV-4, V-1, and V-3; Fig. 1). Sequencing documented

the identical homozygous COL9A2 deletion in the affected brother

(V-3; Figs. 1 and 2) and a heterozygous deletion in the unaffected

brother and parents (V-1, IV-3, and IV-4; Figs. 1 and 2).

DISCUSSION

The clinical findings in the family described here are comparable to

those in STL1, STL2,Marshall syndrome, and in the family with the

homozygous COL9A1mutation (Table I). Patients with the domi-

nantly and recessively inherited forms of Stickler syndrome share

many typical ocular abnormalities and hearing loss. Unlike STL1

and STL2, the patients with the recessive form may have mild,

proportional short stature at least in childhood. Short stature is also

a finding in Marshall syndrome. However, the typical Marshall

syndrome-related facial changes including anteverted nares, mid-

face hypoplasia, and flat nasal bridge do not appear to be as

pronounced in patients with recessive Stickler syndrome.

Oculoskeletal dysplasia segregates as an autosomal recessive trait

in Labrador Retriever and Samoyed dog breeds [Goldstein et al.,

2010]. Two different causative loci have been identified in these

breeds: drd1 and drd2. Recently, a one-base deletion in exon 1 of

COL9A3 was identified co-segregating with drd1. A 1,267 bp dele-

tion inCOL9A2was found to co-segregate with drd2. TheCOL9A2

deletion included part of 50 UTR, all of exon 1, and part of intron 1.The phenotype caused by these mutations in dogs resembles the

phenotype in STL1, STL2, and Marshall syndrome. The main

findings included vitreous dysplasia, retinal detachment, cataracts,

and short-limb dwarfism. The previously described family and

the present family with autosomal recessive Stickler syndrome

have homozygous loss-of-function mutations in COL9A1 and

COL9A2, respectively. Interestingly, the mutations identified in

canine oculoskeletal dyplasia also result in loss-of-function.

Col9a1 knock-out mice have Stickler-related skeletal findings

and hearing loss, thus providing additional support for the role of

loss-of-function mutations in autosomal recessive Stickler syn-

drome [F€assler et al., 1994; Asamura et al., 2005]. It was shown

that the deficiency in a1(IX) chains in mice leads to a functional

knock-out of all polypeptides of collagen IX, even though the

Col9a2 and Col9a3 genes were normally transcribed [Hagg et al.,

1997]. This is further supported by findings from an in vitro co-

expressionof recombinant human collagen IXa chains andprolyl 4

-hydrolylase. In this study, only small amounts of disulfide-bonded

collagen IX homotrimers or heterotrimers of a1(IX) and a3(IX)

FIG. 2. Mutation in COL9A2. Wildtype sequence, homozygous and

heterozygousmutation (c.843_c.846þ 4del8) are shown.Deleted

sequence is indicated in red.

1670 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

chains were observed [Pihlajamaa et al., 1999]. These findings

suggest that loss-of-function of any of the collagen IX a chains

leads to loss-of-function of collagen IX.

Dominant negativemutations in the collagen IX genes have been

shown to result in an autosomal dominant disorder, multiple

epiphyseal dysplasia [Briggs and Chapman, 2002]. Multiple epiph-

yseal dysplasia-2 (EDM2, MIM 120260), EDM3 (MIM 600969),

and EDM6 (MIM 120210) are caused bymutations in theCOL9A2

[Muragaki et al., 1996], COL9A3 [Paassilta et al., 1999a], and

COL9A1 [Czarny-Ratajczak et al., 2001] genes, respectively. The

phenotype is characterized by mildly short stature, epiphyseal

dysplasia mainly affecting the knee joints and early-onset osteoar-

thritis. Unlike Stickler syndrome, eye findings andhearing loss have

not been reported in this disorder. All reported MED mutations

affect splicing of exon 3 of COL9A2 and COL9A3 or exons 8 and

10ofCOL9A1,which result in exon skipping and in-framedeletions

in the COL3 domain. Unlike patients with the dominant negative

MED mutations, the heterozygous carriers of the COL9A1

Arg295Ter, andCOL9A2Asp281GlnfsX70mutations in autosomal

recessive Stickler syndrome families were unaffected. These find-

ings suggest that haploinsufficiency does not lead to phenotypic

consequences.

The findings from the present study and the earlier human,

canine, and mouse studies suggest that mutations in any of the

collagen IX genes can cause autosomal recessive Stickler syndrome.

Findings from these studies also suggest that loss-of-function

mutations in the collagen IX genes cause autosomal recessive

Stickler syndrome.

REFERENCES

AhmadNN, Ala-Kokko L, Knowlton RG, Jimenez SA,Weaver EJ, MaguireJT, TasmanW, Prockop DJ. 1991. Stop codon in the procollagen II gene

as a cause of retinal detachment and arthro-ophthalmopathy (Sticklersyndrome). Proc Natl Acad Sci USA 88:6624–6627.

AnnunenS,K€orkk€o J,CzarnyM,WarmanML,BrunnerHG,K€a€ari€ainenH,Mulliken JB, Tranebjaerg L, Brooks DG, Cox GF, Cruysberg JR, CurtisMA, Davenport SL, Friedrich CA, Kaitila I, Krawczynski MR, Latos-Bielenska A, Mukai S, Olsen BR, Shinno N, Somer M, Vikkula M,Zlotogora J, Prockop DJ, Ala-Kokko L. 1999. Splicing mutations of54 bp exons in the COL11A1 gene cause Marshall syndrome, but othermutations cause overlapping Marshall/Stickler phenotypes. Am J HumGenet 65:974–983.

Asamura K, Abe S, Imamura Y, Aszodi A, Suzuki N, Hashimoto S, TakumiY, Hayashi T, F€assler R, Nakamura Y, Usami S. 2005. Type IX collagen iscrucial for normal hearing. Neuroscience 132:493–500.

Briggs MD, Chapman KL. 2002. Pseudoachondroplasia and multipleepiphyseal dysplasia: Mutation review, molecular interactions, and ge-notype to phenotype correlations. Hum Mutat 19:465–478.

Carter EM, Raggio CL. 2009. Genetic and orthopedic aspects of collagendisorders. Curr Opin Pediatr 21:46–54.

Czarny-RatajczakM,Lohiniva J,RogalaP,KozlowskiK,Per€al€aM,Carter L,Spector TD, Kolodziej L, Sepp€anen U, Glazar R, Kr�olewski J, Latos-Bielenska A, Ala-Kokko L. 2001. A mutation in COL9A1 causes multipleepiphyseal dysplasia. Further evidence for locus heterogeneity in MED.Am J Hum Genet 69:969–980.

Eyre DR. 2002. Collagen of articular cartilage. Arthritis Res 4:30–35.

F€assler R, Schnegelsberg PN, Dausman J, Shinya T,Muragaki Y,McCarthyMT, Olsen BR, Jaenisch R. 1994. Mice lacking alpha 1 (IX) collagendevelop noninflammatory degenerative joint disease. Proc Natl Acad SciUSA 91:5070–5074.

Francomano CA, Liberfarb RM, Hirose T, Maumenee IH, Streeten EA,Meyers DA, Pyeritz RE. 1987. The Stickler syndrome is closely linkedto COL2A1, the structural gene for type II collagen. Genomics 1:293–296.

Goldstein O, Guyon R, Kukekova A, Kuznetsova TN, Pearce-Kelling SE,Johnson J, Aguirre GD, Acland GM. 2010. COL9A2 and COL9A3mutations in canine autosomal recessive oculoskeletal dysplasia. MammGenome 21:398–408.

TABLE I. Clinical Findings

Clinical findingCurrent Family(COL9A2)

Arg295Tera

(COL9A1)STL1 and STL2

(COL2A1 and COL11A1)Marshall Syndrome

(COL11A1)High myopia þ þ þ þVitreoretinal degeneration þ þ þ þRetinal detachment þ � þ þCataracts � � þ þHearing loss þ þ þ þMid-face hypoplasia þ � þ þCleft palate/Pierre Robin sequence � � þ þAnteverted nares � � þ þSmall chin þ � þ þShort stature þb þ þ/� þSpondyloepiphyseal dysplasia NK þ þ þEarly-onset osteoarthritis NK NK þ þOther findings � Genua valga � ��, absent; þ, present; NK, not known.aVan Camp et al. [2006].bNormal adult height.

BAKER ET AL. 1671

Griffith AJ, Sprunger LK, Sirko-Osadsa DA, Tiller GE, Meisler MH,WarmanML. 1998. Marshall syndrome associated with a splicing defectat the COL11A1 locus. Am J Hum Genet 62:816–823.

Hagg R, Hedbom E, M€ollers U, Asz�odi A, F€assler R, Bruckner P. 1997.Absence of the alpha1(IX) chain leads to a functional knock-outof the entire collagen IX protein in mice. J Biol Chem 272:20650–20654.

Hoornaert KP, Vereecke I, Dewinter C, Rosenberg T, Beemer FA, Leroy JG,Bendix L, Bj€orck E, Bonduelle M, Boute O, Cormier-Daire V, De Die-Smulders C, Dieux-Coeslier A, Dollfus H, Elting M, Green A, Guerci VI,Hennekam RC, Hilhorts-Hofstee Y, Holder M, Hoyng C, Jones KJ,Josifova D, Kaitila I, Kjaergaard S, Kroes YH, Lagerstedt K, Lees M,Lemerrer M, Magnani C, Marcelis C, Martorell L, Mathieu M, McEnta-gartM,MendicinoA,Morton J,OrazioG, PaquisV, ReishO, SimolaKO,Smithson SF, Temple KI, Van Aken E, Van Bever Y, van den Ende J, VanHagen JM, Zelante L, Zordania R, De Paepe A, Leroy BP, De Buyzere M,Coucke PJ, Mortier GR. 2010. Stickler syndrome caused by COL2A1mutations: Genotype-phenotype correlation in a series of 100 patients.Eur J Hum Genet 18:872–880.

Levinson G, Gutman GA. 1987. Slipped-strand misparing: A major mech-anism for DNA sequence evolution. Mol Biol Evol 4:203–221.

MajavaM,HoornaertKP,BartholdiD,BoumaMC,BoumanK,CarreraM,DevriendtK,Hurst J, KitsosG,NiedristD, PetersenMB, ShearsD, Stolte-Dijkstra I, VanHagen JM,Ala-Kokko L,M€annikk€oM,MortierGR. 2007.A report on 10 new patients with heterozygous mutations in theCOL11A1 gene and a review of genotype-phenotype correlations in typeXI collagenopathies. Am J Med Genet Part A 143:258–264.

Muragaki Y, Mariman EC, van Beersum SE, Per€al€a M, van Mourik JB,Warman ML, Olsen BR, Hamel BC. 1996. A mutation in the geneencoding the alpha 2 chain of the fibril-associated collagen IX, COL9A2,causes multiple epiphyseal dysplasia (EDM2). Nat Genet 12:103–105.

Myllyharju J, Kivirikko K. 2001. Collagens and collagen-related diseases.Ann Med 33:7–21.

Paassilta P, Lohiniva J, Annunen S, Bonaventure J, LeMerrerM, Pai L, Ala-Kokko L. 1999a. TheCOL9A3 gene: A third locus formultiple epiphysealdysplasia. Am J Hum Genet 64:1036–1044.

Paassilta P, Pihlajamaa T, Annunen S, Brewton RG, Wood BM, JohnsonCC, Liu J, Gong Y, Warman ML, Prockop DJ, Mayne R, Ala-Kokko L.1999b. Complete sequence of 23 kb human COL9A3 gene. Detection ofGly-X-Y triplet deletions that represent neutral variants. J Biol Chem274:22469–22475.

Pihlajamaa T, Vuoristo MM, Annunen S, Per€al€a M, Prockop DJ, Ala-KokkoL. 1998.Twogenes of 90 and15 kb code for similar polypeptides ofthe same collagen molecule. Matrix Biol 17:237–241.

Pihlajamaa T, Per€al€a M, Vuoristo MM, Nokelainen M, Bodo M,Schulthess T, Vuorio E, Timpl R, Engel J, Ala-Kokko L. 1999. Character-ization of recombinant human type IX collagen. Association of achains into homotrimeric and heterotrimeric molecules. J Biol Chem274:22464–22468.

Reginato AM, Olsen BR. 2002. The role of structural genes in the patho-genesis of osteoarthritic disorders. Arthritis Res 4:337–345.

Richards AJ, Yates JRW, Williams R, Payne SJ, Pope FM, Scott JD, SneadMP. 1996. A family with Stickler syndrome type 2 has a mutation in theCOL11A1 gene resulting in the substitution of glycine 97 by valine inalpha-1(XI) collagen. Hum Mol Genet 5:1339–1343.

Richards AJ, McNinch A, Martin H, Oakhill K, Rai H, Waller S, Treacy B,Whittaker J, Meredith S, Poulson A, SneadMP. 2010. Stickler syndromeand the vitreous phenotype: Mutations in COL2A1 and COL11A1. HumMutat 31:E1461–E1471.

Robin NH, Moran RT, Warman M, Ala-Kokko L. 2000. updated 2010Oct 21. Stickler Syndrome. In: Pagon RA, Bird TC, Dolan CR, StephensK, editors. GeneReviews [Internet]. Seattle, WA: University ofWashington.

Shanske AL, Bogdanow A, Shprintzen RJ, Marion RW. 1997. TheMarshallsyndrome: Report of a new family and review of the literature. Am JMedGenet 70:52–57.

Sirko-Osadsa DA, Murray MA, Scott JA, Lavery MA, Warman ML, RobinNH. 1998. Stickler syndrome without eye involvement is caused bymutations in COL11A2, the gene encoding the alpha2(XI) chain of typeXI collagen. J Pediatr 132:368–371.

Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG, Steinberg AG, WardLE. 1965. Hereditary progressive arthro-ophthalmopathy. Mayo ClinProc 40:433–455.

Van Camp G, Snoeckx RL, Hilgert N, van den Ende J, Fukuoka H,Wagatsuma M, Suzuki H, Smets RM, Vanhoenacker F, Declau F, VandeHeyning P, Usami S. 2006. A new autosomal recessive form of Sticklersyndrome is caused by amutation in theCOL9A1 gene. Am JHumGenet79:449–457.

Vuoristo MM, Pappas JG, Jansen V, Ala-Kokko L. 2001. A stop codonmutation in COL11A2 induces exon skipping and leads to overlappingphenotype of hearing loss and non-ocular Stickler syndrome. Am J MedGenet Part A 130:160–164.

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