Ophthalmological Features Associated with COL4A1 Mutations

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OPHTHALMIC MOLECULAR GENETICS

SECTION EDITOR: JANEY L. WIGGS, MD, PhD Ophthalmological Features Associated With COL4A1 Mutations

Isabelle Coupry, PhD; Igor Sibon, MD, PhD; Bruno Mortemousque, MD; Franc¸ois Rouanet, MD; Manuele Mine, PharmD, PhD; Cyril Goizet, MD, PhD

Objective: To investigate the wide variability of ocular Conclusions: The COL4A1 mutations may be associ- manifestations associated with mutations in the COL4A1 ated with various ophthalmologic developmental anoma- gene that encodes collagen IV␣1. lies of anterior segment dysgenesis type, which are reminiscent of Axenfeld-Rieger anomalies (ARA). Cere- Methods: We clinically evaluated 7 patients from 2 un- brovascular disorders should be added to the list of signs related families in whom ocular features segregated with potentially associated with ARA. COL4A1 mutations that were identified by direct sequencing. Clinical Relevance: These data suggest that cerebral magnetic resonance imaging may be recommended in Results: The G2159A transition (c.2159GϾA) that leads the clinical treatment of patients with apparently iso- tothemissensemutationp.Gly720Aspwasidentifiedinfam- lated ARA, even when neurological symptoms or signs ily A. An ocular phenotype of variable severity was observed are lacking. in all affected relatives. The missense mutation c.2263GϾA, p.Gly755Arg was identified in family B. One patient from family B also displayed notable ocular features. Arch Ophthalmol. 2010;128(4):483-489

NEW FORM OF HEREDITARY constellation of ocular findings that in- cerebrovascular disorder clude anomalies of the anterior chamber was recently associated angle and aqueous drainage structures (iri- with mutations in the dogoniodysgenesis), iris hypoplasia, ec- COL4A1 gene that en- centric pupil (corectopia), iris tears (poly- codesA collagen IV␣1.1,2 Mutations in coria), and iridocorneal adhesions COL4A1 were initially associated with ce- traversing the anterior chamber. These rebral microangiopathy (OMIM 607595) anomalies are frequently associated with and familial porencephaly (OMIM a posterior embryotoxon and confer a high 175780).1-4 The clinical spectrum of risk of blindness due to glaucoma.9,10 Author Affiliations: Laboratoire COL4A1 mutations has progressively When extraocular developmental ab- de Geńe´tique Humaine, enlarged in humans as well as mice, normalities that affect the teeth, facial Universite´ Victor Segalen with evidence of neonatal and adult bones, and periumbilical skin are associ- Bordeaux 2, Universite´ intracerebral hemorrhages, aneurysms, ated with ARA, the disorder is named Ax- Bordeaux 2, Bordeaux (Drs Coupry and Goizet); ocular manifestations of variable type, enfeld-Rieger or Rieger syndrome (ARS). 3,5-8 Fe´de´ration des Neurosciences and nephropathy. Patients with ARS may also display hypo- Cliniques (Drs Sibon, Rouanet, Associated ocular features were reti- spadias and, more rarely, hydrocephalus, and Goizet), Service nal arteriolar tortuosity with prominent en- hearing loss, cardiac and kidney abnor- d’ophtalmologie largement of perivascular spaces5 and cata- malities, and congenital hip dislocation (Dr Mortemousque), and ract noted in 3 patients with hereditary anomalies. Other syndromic forms of ARA Service de Geńe´tique Me´dicale porencephaly and adult stroke.3 Our group have been rarely described with addi- (Dr Goizet), Hoˆpital Pellegrin, previously described another family with tional cardiac malformations, sensorineu- Universite´ Bordeaux 2, CHU ocular anterior segment dysgenesis (ASD) ral hearing loss, oculodentodigital dyspla- Bordeaux, Bordeaux; AP-HP, and small-vessel disease of the brain.6 An- sia syndrome, and severe craniosynostosis Laboratoire de Geńe´tique 11-14 Molećulaire, hoˆpital terior segment dysgenesis represents a syndrome. Lariboisière, Paris (Dr Mine); clinically and genetically heterogeneous We present here ocular features asso- INSERM UMR-S 740, Paris, group of disorders.9 The diagnosis of Ax- ciated with COL4A1 mutations in 2 unre- France (Dr Mine). enfeld-Rieger anomaly (ARA) refers to a lated families.

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Patient

Family A Family B

Ophthalmological Signs A.I.1 A.II.1 A.II.2 A.II.3 A.III.1 B.I.1 B.II.1 Corneal opacities − ϩϩ −−−− Corneal neovascularization − − ϩ −−−− Irido-corneal synechiae ϩ − ϩ −−−− Congenital cataract ϩϩϩϩϩϩ/− ϩ Iris anomalies ϩϩϩϩϩ − ϩ Microcornea ϩϩϩϩϩ − ϩ High IOP ϩϩϩ −−−− Glaucoma . . . − ϩ −−−− Optic nerve morphology PA N E NNNN Myopia ϩϩϩ −−−− Retinal detachment − ϩϩ −−−− Macular hemorrhages ϩ −−−−−−

Abbreviations: E, excavation; ellipses, not interpretable; IOP, intraocular pressure; N, normal; PA, peripapillary atrophy; ϩ, present, −, absent.

REPORT OF A CASE Patient A.III.1 was the 8-year-old girl daughter of the proband. At birth, malformations of the eyes were obvi- A detailed description of the personal medical histories ous including a bilateral congenital cataract, iris hypo- and associated neurological phenotypes of family A has plasia, and microcornea (Figure 1C) without congenital been previously published.6 glaucoma. Infantile hemiparesis was noted during the neonatal period.6 At 8 years of age, she presented with FAMILY A strabismus and slight amblyopia of the left eye. Fundus examination did not show optic disc anomalies, retinal The main ocular findings observed in this family are sum- arteriolar tortuosity, or any retinal hemorrhage or exu- marized in Table 1. The G2159A transition (c.2159GϾA) dates. Findings of IOP measurement were normal. leading to the substitution of a glycine by aspartic acid Fluorescein angiography showed no abnormality; the at position 720 (p.Gly720Asp) was identified by direct arteriolar caliber was normal, and there was no leakage sequencing in COL4A1 in all of the affected relatives.6 We of fluorescein or capillary dropout. Neurological exami- have obtained complementary data on the ophthalmo- nation revealed spastic hemiparesis in the right eye with logical history of these relatives and reexamination of the a porencephalic cavity and a diffuse periventricular leu- index case. koencephalopathy on MRI in the left eye (Figure 2C). Patient A.II.1, the index case, was a 38-year-old woman Patient A.I.1 was the 58-year-old mother of the pro- born after uneventful pregnancy and delivery. A bilateral band. She had bilateral iridogoniodysgenesis with irido- congenital cataract with iris hypoplasia was discovered early corneal synechiae, iris hypoplasia, microcornea in life. This bilateral cataract was surgically treated at 12 (Figure 1D), congenital cataract surgery at 55 years of years of age by anterior phakophagia without intraocular age, and high myopia with retinal complications repre- lens implantation. Bilateral aphakia and myopia were cor- sented by bilateral macular hemorrhages. Fundus ex- rected by contact lens use. Her ophthalmological history amination showed peripapillary atrophy, choroidal at- indicated a surgically treated right retinal detachment and rophy, and scars of macular hemorrhages (Fuchs spots) high intraocular pressure (IOP) treated with hypotensive but no arterial tortuosity. Bilateral high IOP was discov- eye drops since 23 years of age. Later, treatment by latano- ered (26 mm Hg) and efficiently treated with hypoten- prost reduced IOP to 16 mm Hg in both eyes (reference sive eye drops. Findings of neurological examination were value, Ͻ21 mm Hg). At 35 years of age, ophthalmological normal. A marked periventricular leukoencephalopa- examination found bilaterally decreased visual acuity pre- thy was obvious on brain MRI (Figure 2B). dominating in the left eye as a consequence of severe am- Patient A.II.2 was the 35-year-old brother of the pro- blyopia. Bilateral microcorneal and peripheral corneal band. His major ophthalmological history included bi- opacities were present with corectopia (Figure 1, A and lateral microcornea, high myopia, congenital cataract, B). Fundus examination showed normal optic discs with- and juvenile glaucoma. The cataract was operated on out retinal hemorrhages or arteriolar tortuosity. The vi- during childhood, with occurrence of bilateral aphakia sual field appeared normal in the right eye and unavail- and severe left amblyopia. At 32 years of age, his IOP able in the left, considering the low visual acuity. She had was 23 to 24 mm Hg bilaterally; the patient was treated a cerebral small deep infarct at 35 years of age. Neuro- with a combination of 3 hypotensive eye drops in the logical examination revealed right spastic hemiparesis and left eye, and he had undergone glaucoma surgery in the a right central facial palsy. Brain magnetic resonance right eye. Ophthalmologic examination showed bilat- imaging (MRI) showed diffuse periventricular leukoen- eral microcornea, central and peripheral corneal opaci- cephalopathy (Figure 2A). ties with corneal neovascularization and iridocorneal

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Figure 1. Ophthalmological features observed in family A. The glance of case A.II.1 is characterized by bilateral microcornea (A) and a postsurgical (congenital cataract) corectopia (B). C, The right eye of case A.III.1 presents microcornea (arrow); the congenital cataract cannot be observed on this photograph. D, The photograph shows the dilated right eye of case A.I.1. It presents microcornea, iris hypoplasia with irregular pupil (arrow). The arrowhead indicates the intraocular lens implant after surgery for congenital cataract. In the right eye of case A.II.2 (E), the microcornea is associated with peripheral corneal opacities and corneal neovascularization (arrow) and triangular pupil (arrowhead) due to iris lesion during the glaucoma surgery. Case A.II.2 also received surgery for congenital cataract without intraocular implant. On the left eye (F), note a corectopia and polycoria with a second small pupil (arrow).

A B C D E

Figure 2. Brain magnetic resonance images obtained in family A. Magnetic resonance imaging fluid-attenuated inversion recovery (A, B, D, and E) and inversion recovery T1-weighted (C) sequences demonstrate a diffuse periventricular leukoencephalopathy in cases A.II.1 (A), A.I.1 (B), A.III.1 (C), A.II.2 (D), and A.II.3 (E). Part C also demonstrates the presence of a porencephaly (arrow) in patient A.III.1.

synechiae, and left corectopia and polycoria (Figure 1, leukoencephalopathy (Figure 2D). At 35 years of age, E and F). Optic nerves showed large excavation due to progression of central corneal opacities and develop- severe glaucoma. Findings of neurological examination ment of refractory ocular hypertension to medical were normal. Brain MRI found a diffuse periventricular therapy in the right eye led to unilateral corneal graft

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Figure 3. Brain magnetic resonance imaging (MRI) obtained in family B. In the index case (patient B.I.1), brain computed tomographic scans performed at a 15-day interval demonstrated 2 brain hemorrhages in the left lenticular nucleus (A) and the right corona radiata (B). On brain MRI, fluid-attenuated inversion recovery sequencing demonstrated diffuse periventricular leukoencephalopathies in patients B.I.1 (C) and B.II.2 (D).

FAMILY B

The main ocular findings observed in this family are sum- marized in Table 1. Direct sequencing of COL4A1 in the index case led to identification of a missense mutation c.2263GϾA, p.Gly755Arg in exon 30. This mutation co- segregated with the disease in all affected relatives. Patient B.I.1, the index case, was a 47-year-old woman. She presented with an acute hemiparesis in the right eye at 47 years of age related to spontaneous left lenticular nucleus hemorrhage. Her medical history included migraine headaches and unexplained white matter leukoencephalopathy. Fifteen days later, she experienced an acute left central facial palsy and dysarthria related to a spontaneous contralateral subcortical cerebral hemorrhage. Brain MRI identified an extended periventricular leukoencephalopathy and 2 recent cerebral hemorrhages but neither small deep infarct nor microbleeding (Figure 3, A-C). Ophthalmological examination revealed severe hyperopia and lens opacities without visual impairment. The anterior chamber of the eyes appeared normal, without cornea and iris abnormality. Fundus examination showed no optic disc anomalies, retinal arteriolar tortuosities, retinal hemorrhages, or exudates. Fluorescein angiography was not performed. Figure 4. Ophthalmological features observed in family B. The image shows isolated prominent Schwalbe line (posterior embryotoxon) without glaucoma Patient B.II.2 was the 10-year-old daughter of the pro- observed in patient B.II.2. band. Bilateral congenital cataract, prominent Schwalbe line (posterior embryotoxon) (Figure 4), and relative microcornea (diameter, 11 mm) without congenital glau- and glaucoma drainage implant (Molteno implant) sur- coma were observed. Fundus examination showed no op- gery. At the time, high IOP (35 mm Hg) in the left eye tic disc anomalies, retinal arteriolar tortuosities, or any was found following poor therapeutic observance. Acute retinal hemorrhages or exudates. Fluorescein angiogra- retinal detachment in the right eye occurred a few weeks phy was not performed. Migraine headaches without aura after the corneal graft, which was surgically treated, with were reported by the patient from 8 years of age. Find- a poor final visual outcome. ings of neurological examination were normal. Brain MRI Patient A.II.3 was the 29-year-old sister of the pro- showed periventricular leukoencephalopathy but no small band. She had strabismus with severe amblyopia in the deep infarct, microhemorrhage, macrohemorrhage, or left eye, and ophthalmologic examination showed a bi- porencephaly were observed (Figure 3D). lateral microcornea and a bilateral cataract that had not received surgery. Her IOP was normal. Fundus examination revealed normal optic discs and retinal vessels. COMMENT Findings of neurological examination were normal. Brain MRI showed a diffuse periventricular leukoencephalopa- We show here that COL4A1 mutations may be associ- thy (Figure 2E). ated with various ophthalmologic developmental anoma-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 2. Type of Mutation and Ophthalmological and Extraocular Findings in Mice With COL4A1 Mutation

Natural Mutant Mice20 Mouse Lineage8

Mouse Background Bru Svc Raw C57BL/6J 129B6F1 B6F1 Mutation in COL4A1 Gly627Trp Gly1064Asp Lys950Glu COL4A1⌬ex40 COL4A1⌬ex40 COL4A1⌬ex40 Ophthalmological signs Iridocorneal angle dysgenesis ϩϩϩ −−ϩϩϩ ϩϩ ϩϩ Corneal opacity ϩ −−ϩ −− Cataract V V − ϩ −− Iridocorneal adhesions ϩ −−ϩϩ − Iris anomalies ϩ −−ϩ −− IOP ND ND ND High N N Ocular globes B N N B N N Optic nerve morphology Excavation ND ND Hypoplasia N N Retinal detachment ϩ Extraocular signs G SBS − CVD − −

Abbreviations: CVD, cerebrovascular disorder; B, buphthalmos; G, glomerulopathy; IOP, intraocular pressure; N, normal; ND, not documented; SBS, small body size; V, vacuolar; ϩϩϩ, severe; ϩϩ, mild; ϩ, present; −, absent.

lies of ASD type that are reminiscent of ARA (Table 1). During development of the tissues that compose an Indeed, ocular features including posterior embryo- anterior eye segment, cells that originate from the sur- toxon, microcornea, cornea opacity, and increased IOP, face epithelium or the neuroepithelium need to interact as well as congenital cataracts, fall into the clinical spec- with mesenchymal cells, which predominately originate trum observed in ARA. from the neural crest.22 This interaction is under the The different ocular anterior chamber anomalies dis- control of a broad range of transcription factors that are played by the affected kindred of families A and B are rel- active in epithelial or mesenchymal cells, or both. In evant to the diagnosis of ARA. Additional ocular signs humans, mutations in PITX2 and FOXC1, 2 genes that not included in the spectrum of ARA malformations were encode transcription factors specifically expressed in the observed. Microcornea was noted in patients from both mesenchymal cells, result in a broad spectrum of abnor- families and may consequently be considered character- malities during anterior eye development.16,17,23,24 Most istic of this familial eye developmental condition. Alter- of these phenotypes belong to the broad spectrum of fea- natively, the presence of severe hyperopia observed in tures that are part of ARA/ARS.10 The PAX6 gene, which the index case of family B (B.I.1) may reflect a fortu- codes for a paired domain and pairedlike homeodomain itous association considering the high prevalence of hy- transcription factor, is also critically required for the peropia in general population. The link between ASD and morphogenesis of mesenchyme-derived tissues in the potentially severe myopia found in 3 patients in family anterior eye.25 Patients with heterozygote mutations in A (A.I.1, A.II.1, A.II.2) is more hypothetical. Retinal com- PAX6 exhibit the phenotype of aniridia that may vari- plications present in the same 3 patients should instead ably include iris hypoplasia, corneal opacification, cata- be considered as complications of severe myopia and apha- ract, and foveal dysplasia.15,26 The phenotypes associated kia. The diagnosis of glaucoma was retained in only 1 with PAX6 mutations overlap with those of ARA/ARS.27 patient (A.II.2), as interpretation of visual fields was im- The genetic cause of ARA/ARS in humans was so far possible considering the low visual acuity of patient A.I.1. solely associated with molecular defects in transcription The IOP was high in another patient (A.II.1), with no factors. alteration of visual fields. There was no evidence of op- However, it has been demonstrated that mutations tic nerve hypoplasia in any patient. in basement membrane components may cause ASD. Axenfeld-Rieger anomaly is genetically heterogeneous In humans, mutations in laminin-␤2 lead to congeni- because mutations in 3 genes, PITX2 (on chromosome tal nephrotic syndrome and ASD that differs from 4q25), FOXC1 (also named FKHL7) (6p25), and PAX6 ARA.28 More interestingly, mutant mice that manifest (11p13), have been identified to date.15-17 An additional lo- ASD of possible ARA type have also been de- cus has been proposed on chromosome 13q14.18 Patho- scribed.8,20,21,29 Most of the mice had a mutation in the genic alleles of these developmental genes often cause a spec- COL4A1 gene; detailed ophthalmological findings are trum of ocular phenotypes that vary in severity.19 In 2005, available (Table 2).8,20 The phenotypic presentation of Van Agtamel et al20 described iris/corneal adhesions, buph- the COL4A1⌬ex40 mutant mice on the C57BL/6J genetic thalmos, iris defects, corneal opacity, and cataracts in background is similar to the phenotype of family A, ex- COL4A1 mutant mouse models, suggesting a potential link cept for the nerve optic hypoplasia only observed in mice.8 between ARA and COL4A1 mutations in humans. Very re- Other mice carrying heterozygous COL4A1 missense mu- cently, other studies in mice have focused on the role of tations showed a very wide spectrum of ophthalmologi- COL4A1 in abnormal ocular development.8,21 Finally, we cal phenotypes including microphthalmia, buphthal- previously described family A as the first with inherited syn- mos, anterior polar opacity with or without cornea-lens dromic ocular ASD corresponding to ARA of variable se- adhesion, corneal opacities, lens vacuoles, and total lens verity, caused by mutation in COL4A1.6 opacity.21

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Members of the type IV collagen family are essential Role of the Sponsor: The experimental work was per- components of all basement membranes and define struc- formed on the Plateforme Geńotypage Se´quençage of Bor- tural stability as well as tissue-specific functions.30 Type deaux and Laboratoire de Geńe´tique de l’hoˆpital Lari- IV collagen is also crucial for the initial formation of boisière; the Plateforme Geńotypage Se´quençage was basement membranes during embryonic develop- constituted using grants from the Conseil Re´gional ment.31 In mice, COL4A1 was detected in the basement d’Aquitaine and the FEDER. membrane underlying the lens pit during early embry- Additional Contributions: The authors are grateful to onic development and in both the anterior and poste- the family members who participated in this study. The rior lens capsules of the lens vesicle both later in devel- authors thank Ingrid Burgelin for her technical contri- opment and in newborn and adult mice. Similar bution to this study, and Isabelle Orignac, MD, Jean- abundant expression of COL4A1 was determined in hu- Marc Orgogozo, MD, Elizabeth Tournier-Lasserve, MD, man embryonic and adult lens capsules.32 The differen- PhD, Didier Lacombe, MD, and Benoıˆt Arveiler, PharmD, tiation of mesenchymal cells in the cornea and the for- PhD, for reviewing and commenting on the article and mation of an anterior chamber depend on signals for helpful discussions. controlled by transcription factors (such as PITX2 and FOXC1) that are specifically expressed in the mesenchymal cells and on inductive signals from the lens.8,33 REFERENCES Mutations in COL4A1 may disrupt some lenticular sig- naling in the direction of mesenchymal cells. The link 1. Gould DB, Phalan FC, Breedveld GJ, et al. 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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 21. Favor J, Gloeckner CJ, Janik D, et al. Type IV procollagen missense mutations congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. associated with defects of the eye, vascular stability, the brain, kidney function Hum Mol Genet. 2004;13(21):2625-2632. and embryonic or postnatal viability in the mouse, Mus musculus: an extension 29. Ylikärppä R, Eklund L, Sormunen R, et al. Lack of type XVIII collagen results in of the Col4a1 allelic series and the identification of the first two Col4a2 mutant anterior ocular defects. FASEB J. 2003;17(15):2257-2259. alleles. Genetics. 2007;175(2):725-736. 30. Kalluri R. Basement membranes: structure, assembly and role in tumour 22. Cvekl A, Tamm ER. Anterior eye development and ocular mesenchyme: new in- angiogenesis. Nat Rev Cancer. 2003;3(6):422-433. sights from mouse models and human diseases. Bioessays. 2004;26(4):374- 31. Pöschl E, Schlotzer-Schrehardt U, Brachvogel B, Saito K, Ninomiya Y, Mayer U. 386. Collagen IV is essential for basement membrane stability but dispensable for ini- 23. Doward W, Perveen R, Lloyd IC, Ridgway AE, Wilson L, Black GC. A mutation in tiation of its assembly during early development. Development. 2004;131(7): the RIEG1 gene associated with Peters’ anomaly. J Med Genet. 1999;36(2): 1619-1628. 152-155. 32. Kelley PB, Sado Y, Duncan MK. Collagen IV in the developing lens capsule. Ma- 24. Nishimura DY, Searby CC, Alward WL, et al. A spectrum of FOXC1 mutations trix Biol. 2002;21(5):415-423. suggests gene dosage as a mechanism for developmental defects of the ante- 33. Genis-Galvez JM. Role of the lens in the morphogenesis of the iris and cornea. rior chamber of the eye. Am J Hum Genet. 2001;68(2):364-372. Nature. 1966;210(5032):209-210. 25. Ashery-Padan R, Gruss P. Pax6 lights-up the way for eye development. Curr Opin 34. Hjalt TA, Amendt BA, Murray JC. PITX2 regulates procollagen lysyl hydroxylase Cell Biol. 2001;13(6):706-714. (PLOD) gene expression: implications for the pathology of Rieger syndrome. J Cell 26. Jordan T, Hanson I, Zaletayev D, et al. The human PAX6 gene is mutated in two Biol. 2001;152(3):545-552. patients with aniridia. Nat Genet. 1992;1(5):328-332. 35. Heikkinen J, Toppinen T, Yeowell H, et al. Duplication of seven exons in the lysyl 27. Prosser J, van Heyningen V. PAX6 mutations reviewed. Hum Mutat. 1998;11(2): hydroxylase gene is associated with longer forms of a repetitive sequence within 93-108. the gene and is a common cause for the type VI variant of Ehlers-Danlos syndrome. 28. Zenker M, Aigner T, Wendler O, et al. Human laminin beta2 deficiency causes Am J Hum Genet. 1997;60(1):48-56.

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