Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function

TY - JOUR

T1 - Case report

T2 - a novel KERA mutation associated with cornea plana and its predicted effect on protein function

AU - Roos, Laura

AU - Bertelsen, Birgitte

AU - Harris, Pernille

AU - Bygum, Anette

AU - Jensen, Hanne

AU - Grønskov, Karen

AU - Tümer, Zeynep

PY - 2015/6/23

Y1 - 2015/6/23

N2 - 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.

AB - 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.

KW - Adult

KW - Base Sequence

KW - Child

KW - Cornea

KW - Corneal Diseases

KW - Eye Diseases, Hereditary

KW - Female

KW - Humans

KW - Hyperopia

KW - Hypotrichosis

KW - Male

KW - Models, Chemical

KW - Mutation, Missense

KW - Pedigree

KW - Protein Conformation

KW - Proteoglycans

KW - Sequence Analysis, DNA

KW - Turkey

KW - Young Adult

U2 - 10.1186/s12881-015-0179-9

DO - 10.1186/s12881-015-0179-9

M3 - Journal article

C2 - 26099342

SN - 1471-2350

VL - 16

SP - 1

EP - 6

JO - B M C Medical Genetics

JF - B M C Medical Genetics

M1 - 16:40

ER -