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Genetic mapping of retinal degenerations in Northern Sweden
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. (Golovleva/Sandgren)
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 [en]
Bothnia dystrophy; cone dustrophy; linkage analysis; mutation; PITPNM3; PRPF31; retinitis pigmentosa; RLBP1
National Category
Medical Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:umu:diva-27004ISBN: 978-91-7264-887-6 (print)OAI: oai:DiVA.org:umu-27004DiVA: diva2:275603
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
List of papers
1. Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families
Open this publication in new window or tab >>Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families
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2007 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 6, 664-671 p.Article in journal (Refereed) Published
Abstract [en]

Autosomal dominant cone dystrophy (CORD5) (MIM 600977) is a rare disease predominantly affecting cone photoreceptors. Here we refine the CORD5 locus previously mapped to 17p13 from 27 to 14.3 cM and identified a missense mutation, Q626H in the phosphatidylinositol transfer (PIT) membrane-associated protein (PITPNM3) (MIM 608921) in two Swedish families. PITPNM3, known as a human homologue of the Drosophila retinal degeneration B (rdgB), lacks the N-terminal PIT domain needed for transport of phospholipids, renewal of photoreceptors membrane and providing the electroretinogram (ERG) response to light. In our study, the mutation causing CORD5 is located in the C-terminal region interacting with a member of nonreceptor protein tyrosine kinases, PYK2. Our finding on the first mutation in the human homologue of Drosophila rdgB indicates novel pathways and a potential important role of the PITPNM3 in mammalian phototransduction.

Place, publisher, year, edition, pages
Nature publishing group, 2007
Keyword
cone rod dystrophy; PITPNM3;rdgB; missense mutation
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-26970 (URN)10.1038/sj.ejhg.5201817 (DOI)
Available from: 2009-11-05 Created: 2009-11-04 Last updated: 2017-12-12Bibliographically approved
2. Low mutation rate in PITPNM3 in cone/cone-rod dystrophies
Open this publication in new window or tab >>Low mutation rate in PITPNM3 in cone/cone-rod dystrophies
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-26985 (URN)
Available from: 2009-11-05 Created: 2009-11-05 Last updated: 2010-01-14Bibliographically approved
3. Breakpoint characterization of a novel ~59 kb genomic deletion on 19q13.42 in autosomal dominant retinitis pigmentosa with reduced penetrance
Open this publication in new window or tab >>Breakpoint characterization of a novel ~59 kb genomic deletion on 19q13.42 in autosomal dominant retinitis pigmentosa with reduced penetrance
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2009 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, no 5, 651-655 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.

Place, publisher, year, edition, pages
Nature publishing group, 2009
Keyword
PRPF31; retinitis pigmentosa; RP11; deletion; haploinsufficiency
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-26979 (URN)10.1038/ejhg.2008.223 (DOI)
Available from: 2009-11-05 Created: 2009-11-05 Last updated: 2017-12-12Bibliographically approved
4. Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1
Open this publication in new window or tab >>Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1
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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
Keyword
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:nbn:se:umu:diva-26981 (URN)10.1167/iovs.07-1664 (DOI)000257124000051 ()
Available from: 2009-11-05 Created: 2009-11-05 Last updated: 2017-12-12Bibliographically approved

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