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Case Report: a Novel KERA Mutation Associated with Cornea Plana and Its Predicted Effect on Protein Function

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Case Report: a Novel KERA Mutation Associated with Cornea Plana and Its Predicted Effect on Protein Function University of Southern Denmark Case report a novel KERA mutation associated with cornea plana and its predicted effect on protein function Roos, Laura; Bertelsen, Birgitte; Harris, Pernille; Bygum, Anette; Jensen, Hanne; Grønskov, Karen; Tümer, Zeynep Published in: B M C Medical Genetics DOI: 10.1186/s12881-015-0179-9 Publication date: 2015 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Roos, L., Bertelsen, B., Harris, P., Bygum, A., Jensen, H., Grønskov, K., & Tümer, Z. (2015). Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function. B M C Medical Genetics, 16(1), [40]. https://doi.org/10.1186/s12881-015-0179-9 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 29. Sep. 2021 Roos et al. BMC Medical Genetics (2015) 16:40 DOI 10.1186/s12881-015-0179-9 CASE REPORT Open Access Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function Laura Roos1*, Birgitte Bertelsen1, Pernille Harris2, Anette Bygum3, Hanne Jensen4, Karen Grønskov1 and Zeynep Tümer1 Abstract Background: Cornea plana (CNA) is a hereditary congenital abnormality of the cornea characterized by reduced corneal curvature, extreme hypermetropia, corneal clouding and hazy corneal limbus. The recessive form, CNA2, is associated with homozygous or compound heterozygous mutations of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described. Case presentation: In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation is predicted to destabilize the structure of keratocan, leading to the classical ocular phenotype in the affected individuals. All the four known missense mutations, including the variation found in this family, affect the conserved residues of the leucine rich repeat domain of keratocan. These mutations are predicted to result in destabilization of the protein. Conclusion: We present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function, and this knowledge will ease the interpretation of future findings of mutations in these areas in other families with cornea plana. Keywords: Cornea plana 2, Hypotrichosis, KERA protein, Missense mutation, Protein modelling, Leucin rich repeat domain Background adhesions between cornea and iris [1–4]. The gene de- Cornea plana is a rare hereditary congenital abnormality fective in CNA1 has not been identified yet, while of the cornea characterized by reduced corneal curva- homozygous or compound heterozygous mutations in ture, extreme hypermetropia, corneal clouding and hazy the keratocan gene (KERA) on chromosome 12q22 are corneal limbus. There is an autosomal dominant (CNA1; shown to cause CNA2 [5]. The protein encoded by OMIM 121400) and a more severe autosomal recessive KERA, keratocan, is a keratan sulfate proteoglycan with form (CNA2; OMIM 217300) of the disorder. The reces- a core of leucine-rich repeats (LRR), flanked by clusters sive form is more frequently associated with additional of cystein, essential to maintain the three-dimensional ocular manifestations, such as iris malformation and structure of the protein. Keratocan is an extracellular matrix molecule of the corneal stroma that is important for normal cornea morphogenesis and involved in main- * Correspondence: [email protected] taining corneal transparency [6]. Studies with mice show 1Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup 2600, Denmark expression of this gene during eye development and in Full list of author information is available at the end of the article © 2015 Roos et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Roos et al. BMC Medical Genetics (2015) 16:40 Page 2 of 6 adult mice, it is exclusively expressed in the cornea Case presentation [7]. To date, only nine different disease-associated Clinical studies KERA mutations have been reported in various popu- A pedigree of the family is shown in Fig. 1a. The index lations [5, 8–11]: Three nonsense mutations, four mis- individuals (IV:4 and IV:5) are dizygotic male twins, who sense mutations, one splice-site mutation, and one were 11 years old at the time of clinical examination. frameshift (single-nucleotide deletion) mutation. All They were born at gestational age 36 to healthy and un- the reported missense mutations are within the LRR related parents. Birth weights were 2300 g (IV:4) and domain, which is considered to be essential for the 2352 g (IV:5). Shortly after birth, IV:4 and IV:5 were binding between keratocan and the collagen fibrils in found to be excessive hypermetropic (+11,75D/+11,75D the corneal matrix during development. A disruption and 12,75D/+13,75D) and both had corneal clouding of the protein affects both the structure and the trans- and flat corneas. The boys have been wearing glasses parency of the cornea [12]. since the age of 3 months, and have been monitored fre- In this report, we present the clinical data and de- quently. The clouding of the corneas decreased over the scribe a new KERA mutation in a Turkish family with first 8 months of life. Clinical and eye examinations were autosomal recessive cornea plana. We suggest the gen- carried out at the age of 10 years showing hazy corneal etic variation to result in destabilization of the protein limbi with vessels were noticed (Fig. 1c). IV:4 has a small structure. We furthermore apply protein modelling to temporal iridocorneal synechi. Axial lengths were within predict the effect of the missense mutations on the normal range (A-scan using Hiscan opticon). ERG, mo- structure of keratocan. tility, pupillary reaction, funduscopy and intraocular A < < I 1 234< II < 3 < 4 < < 4 1 23 4 5 6 7 8 III < 4 < < < < 1 2 3* 4** 5 6 * 7 8 9 * 10 * 11 12 IV 9 < 2 2 123* 456 7 89 Cornea plana Heterozygote forc.674T>C V Investigated for c.674T>C 1 2 Hair loss * BCD IV:3 IV:4 IV:4 Fig. 1 Family with cornea plana. a. The pedigree is consistent with autosomal recessive inheritance; b. The right eye of patient IV:3, with a small, malformed pupil, and a hazy corneal limbus; c. The eyes of patient IV:4; d. The scalp of patient IV:4 at age 11, showing hypotrichosis on the anterior part of vertex Roos et al. BMC Medical Genetics (2015) 16:40 Page 3 of 6 pressure were normal. Keratometry (Zeiss keratometer) BigDye Terminator v3.1 Cycle Sequencing Kit (Applied showed bilateral flat corneas and high astigmatism in Biosystems, Foster City, CA). Sequencing products were both boys (Additional file 1: Table S1). purified and run on an ABI 3130 XL genetic analyzer The boys’ general development has been in the lower (AppliedBiosystems). Sequences of the coding exons and range of normal. They attend a normal school at normal 10 bp of the flanking introns were analyzed using SeqS- age level, but perform in the low end of their class. They cape software (AppliedBiosystems). Primer sequences both have slight behavioural problems and motor tics, and PCR conditions are available on request. which are also found in their unaffected younger A novel missense mutation was detected in exon 2 of brother. From the age of 9 years IV:4 has experienced KERA, c.674T>C, which is predicted to result in sub- progressive frontal hair loss on vertex, the hair being stitution of isoleucine at position 225 with threonine, lighter in colour and lusterless (Fig. 1d). Hair micros- p.(Ile225Thr). All affected family members investigated copy was normal without any signs of hair shaft dis- for the mutation (IV:3, IV:4 and IV:5) were homozygous, order. IV:5 has slight general hypermobility and pes while the clinically unaffected parents (III: 3 and III:4), planus. the brother (IV:6), a maternal aunt (III:7) and a maternal uncle (III:5) were all heterozygous for the mutation. Family history The mutation is absent from the 1000 Human Genome There were several affected individuals in the family, and [13] and NHLBI Exome Sequencing [14] databases. The the pedigree was suggestive of autosomal recessive in- Ile225 lies within the LRR domain and is a highly con- heritance (Fig. 1a). Clinical information of the individ- served amino acid.
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