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Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. (Golovleva/Sandgren)
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. (Golovleva/Sandgren)
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik. (Golovleva/Sandgren)
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. (Golovleva/Sandgren)
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2007 (Engelska)Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, nr 6, s. 664-671Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Nature publishing group , 2007. Vol. 15, nr 6, s. 664-671
Nyckelord [en]
cone rod dystrophy; PITPNM3;rdgB; missense mutation
Nationell ämneskategori
Medicinsk genetik
Forskningsämne
genetik
Identifikatorer
URN: urn:nbn:se:umu:diva-26970DOI: 10.1038/sj.ejhg.5201817OAI: oai:DiVA.org:umu-26970DiVA, id: diva2:275367
Tillgänglig från: 2009-11-05 Skapad: 2009-11-04 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Genetic mapping of retinal degenerations in Northern Sweden
Öppna denna publikation i ny flik eller fönster >>Genetic mapping of retinal degenerations in Northern Sweden
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå university, 2009. s. 76
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1305
Nyckelord
Bothnia dystrophy; cone dustrophy; linkage analysis; mutation; PITPNM3; PRPF31; retinitis pigmentosa; RLBP1
Nationell ämneskategori
Medicinsk genetik
Forskningsämne
genetik
Identifikatorer
urn:nbn:se:umu:diva-27004 (URN)978-91-7264-887-6 (ISBN)
Distributör:
Medicinsk och klinisk genetik, 901 85, Umeå
Disputation
2009-11-27, Building 1D, 9th floor, room B, NUS, 901 85 Umeå, NUS, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-11-09 Skapad: 2009-11-06 Senast uppdaterad: 2018-01-12Bibliografiskt granskad

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Köhn, LindaKadzhaev, KonstantinBurstedt, Marie SIHaraldsson, SusannHallberg, BengtSandgren, OlaGolovleva, Irina

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Köhn, LindaKadzhaev, KonstantinBurstedt, Marie SIHaraldsson, SusannHallberg, BengtSandgren, OlaGolovleva, Irina
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