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Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
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2008 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 49, no 7, 3172-3177 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Bothnia dystrophy (BD) is an autosomal recessive retinitis pigmentosa (arRP) associated with the c.700C>T mutation in the RLBP1 gene. Testing of patients with BD has revealed the c.700C>T mutation on one or both alleles. The purpose of this study was to elucidate the underlying genetic mechanisms along with a clinical evaluation of the heterozygous patients with BD.

Methods: Patients with BD heterozygous for the RLBP1 c.700C>T were tested for 848 mutations by arrayed primer-extension technology. Further mutation detection was performed by PCR-restriction fragment length polymorphism (RFLP), sequencing, denaturing (d)HLPC and allelic discrimination. The ophthalmic examinations were performed in all c.700C>T heterozygotes.

Results: The clinical findings in 10 BD heterozygotes were similar to those in the homozygotes. The presence of a second mutation, c.677T>A, corresponding to p.M226K was detected in all 10 cases. Segregation analysis showed that the mutations were allelic, and the patients were compound heterozygotes [c.677T>A]+[c.700C>T]. One of those patients was also a carrier of the c.40C>T corresponding to the p.R14W change in carbonic anhydrase IV (CAIV) associated with autosomal dominant RP, RP17. His mother, a carrier of the identical change was declared healthy after ophthalmic examination. This sequence variant was found in 6 of 143 tested blood donors.

Conclusions: The high frequency of arRP in northern Sweden is due to two mutations in the RLBP1 gene: c.677T>A and c.700C>T. BD is caused by the loss of CRALBP function due to changed physical features and impaired activity of retinoid binding. The CAIV p.R14W sequence variant found in one of the patients with a BD phenotype is a benign polymorphism in a population of northern Sweden.

Place, publisher, year, edition, pages
Association for Research in Vision and Ophthalmology , 2008. Vol. 49, no 7, 3172-3177 p.
Keyword [en]
Adolescent, Adult, Aged, Aged; 80 and over, Alleles, Amino Acid Substitution, Arginine, Carbonic Anhydrase IV/*genetics, Carrier Proteins/*genetics, Child, Cytosine, Female, Fundus Oculi, Genes; Recessive, Heterozygote, Homozygote, Humans, Male, Middle Aged, Mutation, Phenotype, Retinitis Pigmentosa/*genetics/pathology/physiopathology, Thymine, Tryptophan
National Category
Medical Genetics Ophthalmology
Research subject
Ophtalmology; Genetics
Identifiers
URN: urn:nbn:se:umu:diva-26981DOI: 10.1167/iovs.07-1664ISI: 000257124000051OAI: oai:DiVA.org:umu-26981DiVA: diva2:275378
Available from: 2009-11-05 Created: 2009-11-05 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Genetic mapping of retinal degenerations in Northern Sweden
Open this publication in new window or tab >>Genetic mapping of retinal degenerations in Northern Sweden
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inherited retinal degenerations are a group of disorders characterised by great genetic heterogeneity. Clinically, they can be divided into two large groups of diseases, those associated with night blindness, e.g. retinitis pigmentosa (RP), and those with macular malfunction, e.g. cone/cone-rod dystrophy (COD/CORD). This thesis is focused on finding the genetic basis of disease in families with autosomal dominant COD, autosomal dominant RP, and Bothnia dystrophy (BD), a regional variant of RP. 

 A variant of COD was previously mapped to 17p12-p13 in a family from northern Sweden. One additional family originating from the same geographical area was included in fine mapping of this chromosome region. Using 12 microsatellite markers in linkage and haplotype analysis, the region was refined from 26.9 to 14.3 cM. A missense mutation, Q626H, in an evolutionarily conserved region of PITPNM3, phosphatidylinositol transfer membrane-associated protein, was identified. The mutation segregated with the disease in both families and was absent from normal control chromosomes. PITPNM3 is a human homologue of the Drosophila retinal degeneration (rdgB) protein, which is highly expressed in the retina and has been proposed to be required for membrane turnover of photoreceptor cells.

With the intention of establishing the global impact that PITPNM3 has on retinal degenerations 165 DNA samples from COD and CORD patients were obtained from Denmark, Germany, the UK, and USA and screened for mutations. The Q626H mutation found in the Swedish families was also found in one British family and a novel Q342P variant was detected in a German patient. In addition, two intronic variants were identified: c.900+60C>T and c.901-45G>A. Thus, we concluded that mutations in PITPNM3 represent a rare cause of COD worldwide.

In two large families from northern Sweden showing autosomal dominant RP with reduced penetrance, the disease locus was mapped using genome-wide linkage analysis to 19q13.42 (RP11). Since mutation screening of eight genes on 19q13.42 revealed no mutations, multiplex ligation-dependent probe amplification (MLPA) was used to screen for large genomic abnormalities in PRPF31, RHO, RP1, RPE65, and IMPDH1. A large deletion spanning 11 exons of PRPF31 and three genes upstream was identified. Using long-range PCR, the breakpoints of the deletion were identified and the size of the deletion was determined to encompass almost 59 kb.

BD is an autosomal recessive type of RP with high prevalence in northern Sweden. The disease is associated with a c.700C>T mutation in RLBP1. In a screening of recessive RP in northern Sweden, 67 patients were found to be homozygous for c.700C>T and 10 patients were heterozygous. An evaluation with arrayed primer extension (APEX) technology revealed a second mutation, c.677T>A, in RLBP1 giving rise to compound heterozygosity in these patients. In addition, a c.40C>T exchange in CAIV was detected in a patient with BD and in 143 healthy blood donors. The c.40C>T substitution in CAIV has been reported to cause autosomal dominant RP in South African families with European ancestry. However, in the population of northern Sweden it appears to be a benign polymorphism.

In summary, a first mutation in PITPNM3, encoding a human homologue of the Drosophila retinal degeneration protein, was detected in two large families with COD. A large deletion in PRPF31 was discovered in two families with autosomal dominant RP showing reduced penetrance and in 10 patients BD was shown to be caused by two allelic mutations in RLBP1.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2009. 76 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1305
Keyword
Bothnia dystrophy; cone dustrophy; linkage analysis; mutation; PITPNM3; PRPF31; retinitis pigmentosa; RLBP1
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-27004 (URN)978-91-7264-887-6 (ISBN)
Distributor:
Medicinsk och klinisk genetik, 901 85, Umeå
Public defence
2009-11-27, Building 1D, 9th floor, room B, NUS, 901 85 Umeå, NUS, 09:00 (English)
Opponent
Supervisors
Available from: 2009-11-09 Created: 2009-11-06 Last updated: 2010-01-18Bibliographically approved
2. Underlying genetic mechanisms of hereditary dystrophies in retina and cornea
Open this publication in new window or tab >>Underlying genetic mechanisms of hereditary dystrophies in retina and cornea
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inherited retinal and corneal dystrophies represent a group of disorders with great genetic heterogeneity. Over 250 genes are associated with retinal diseases and 16 genes are causative of corneal dystrophies. This thesis is focused on finding the genetic causes of corneal dystrophy, Leber congenital amaurosis (LCA), Stargardt disease and retinitis pigmentosa in families from northern Sweden.  By whole exome sequencing a novel mutation, c.2816C>T, p.Thr939Ile, in Collagen Type XVII, Alpha 1 chain, COL17A1, gene was identified in several families with epithelial recurrent erosion dystrophy (ERED). We showed that the COL17A1 protein is expressed in the basement membrane of the cornea, explaining the mutation involvement in the corneal symptoms. We could link all the families in this study to a couple born in the late 1700s confirming a founder mutation in northern Sweden. Our finding highlights role of COL17A1 in ERED and suggests screening of this gene in patients with similar phenotype worldwide. Furthermore the genetic causes in several retinal degenerations were identified. In one family with two recessive disorders, LCA and Stargardt disease, a novel stop mutation, c.2557C>T, p.Gln853Stop, was detected in all LCA patients. In the Stargardt patients two intronic variants, the novel c.4773+3A>G and c.5461-10T>C, were detected in the ABCA4 gene. One individual was homozygous for the known variant c.5461-10T>C and the other one was compound heterozygote with both variants present. Both variants, c.4773+3A>G and c.5461-10T>C caused exon skipping in HEK293T cells demonstrated by in vitro splice assay, proving their pathogenicity in Stargardt disease. Finally, in recessive retinitis pigmentosa, Bothnia Dystrophy (BD), we identified a second mutation in the RLBP1 gene, c.677T>A, p.Met226Lys. Thus, BD is caused not only by common c.700C>T variant but also by homozygosity of c.677T>A or compound heterozygosity. Notably, known variant, c.40C>T, p.R14W in the CAIV gene associated with a dominant retinal dystrophy RP17 was detected in one of the compound BD heterozygote and his unaffected mother. This variant appears to be a benign variant in the population of northern Sweden.

In conclusion, novel genetic causes of retinal dystrophies in northern Sweden were found demonstrating the heterogeneity and complexity of retinal diseases. Identification of the genetic defect in COL17A1 in the corneal dystrophy contributes to understanding ERED pathogenesis and encourages refinement of IC3D classification. Our results provide valuable information for future molecular testing and genetic counselling of the families.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2017. 57 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1872
Keyword
Cornea, retina, gene, mutation detection, inherited diseases
National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-130538 (URN)978-91-7601-626-8 (ISBN)
Public defence
2017-02-17, Major Groove, Målpunkt J-11, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2017-01-27 Created: 2017-01-23 Last updated: 2017-02-01Bibliographically approved

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