Genotyp-Phänotyp-Korrelation bei Patienten mit PRPH2-Mutationen

Zusammenfassung

Hintergrund: Das Peripherin-Gen (PRPH2) codiert für Peripherin-2, ein photorezeptorspezifisches Transmembranprotein. In der Netzhaut ist Peripherin-2 von entscheidender Bedeutung für die Entwicklung, Anordnung und den Strukturerhalt der Außensegmente der Stäbchen und Zapfen. Bis heute wurden über 90 verschiedene Mutationen innerhalb des PRPH2-Gens gefunden, die verschiedene Formen von Makula- und Netzhautdegenerationen sowie Retinopathia pigmentosa auslösen können. Patienten/Material und Methoden: Bei dieser Studie handelt es sich um eine retrospektive Beobachtungsstudie. In 5 Monaten wurden 3 Patienten aus der ophthalmogenetischen Sprechstunde der Augenklinik der Universität eingeschlossen. Die Patienten wurden für mindestens 8 Monate weiterbeobachtet. Im Rahmen der Beobachtung wurden diverse klinische und apparative Untersuchungen durchgeführt. Die erhobenen Daten umfassten Anamnese, Stammbaumanalyse, augenärztliche Untersuchung, Fundusfotografie, Autofluoreszenz, optische Kohärenztomografie, Farbtest nach Arden, Goldmann-Perimetrie sowie ausführliche elektrophysiologische Untersuchungen. Zudem erfolgte eine Blutentnahme zur genetischen Mutationsanalyse von PRPH2, ABCA4, BEST1, C1QTNF5, CDH3, CNGB3, ELOVL4, FSCN2, PROM1, RDH12, RP1L1, RPGR, TIMP3. Ergebnisse: Die Patienten zeigten interindividuell verschiedene klinische Bilder einer Makuladegeneration. Die Sehschärfe lag zwischen 1/50 im Metervisusbereich bis hin zu 0,8 p [dec]. Die Patienten wiesen typische Elektroretinogramme auf. Die PRPH2-Mutationen waren autosomal-dominant. Eine Familie war heterozygot für die bereits vorbeschriebene Missense-Mutation im PRPH2-Gen: c.514C>T, p.R172W. Der andere Patient war heterozygot für die bislang nicht vorbeschriebene PRPH2-Mutation c.74_77delGGTT, p.W25SfsX12, die aufgrund der Deletion von 4 Basenpaaren zu einem Frameshift und damit zu einem deutlich verkürzten und höchstwahrscheinlich funktionslosen Protein führt. Alle Patienten zeigten eine hohe interindividuelle phänotypische Variabilität. Schlussfolgerung: Die Studie präsentiert erstmals den Phänotyp der bislang unbeschriebenen Frameshift-Mutation c.74_77delGGTT, p.W25SfsX12 im PRPH2-Gen sowie die unterschiedliche phänotypische Ausprägung innerhalb einer Familie mit der seit Langem beforschten R172W-Mutation. Fundusautofluoreszenz, optische Kohärenztomografie und elektrophysiologische Untersuchungen sind wertvolle Instrumente zur Diagnose und zur Evaluation makulärer Netzhauterkrankungen bei PRPH2-Mutationen.

Abstract

Background: The peripherin-2 (PRPH2) gene encodes a photoreceptor-specific transmembrane-protein called peripherin-2 which is critical for the formation and maintenance of rod and cone outer segments. Over 90 different disease-causing mutations in PRPH2 have been identified which cause a variety of forms of macular degeneration and also retinopathia pigmentosa. Patients/Material and Methods: This study is a retrospective observational study of 3 patients ascertained over a 5 month period in the ophthalmogenetic consultation of the university ophthalmic clinic. So far, the patients were followed for 8 months at least. Data examined included clinical history, pedigree analysis, ophthalmological examination, fundus photography, autofluorescence imaging, optical coherence tomography, Arden colour test, Goldmann perimetry and detailed electrophysiological assessment. Blood samples were taken for DNA extraction and mutation analysis of PRPH2 and ABCA4, BEST1, C1QTNF5, CDH3, CNGB3, ELOVL4, FSCN2, PROM1, RDH12, RP1L1, RPGR, TIMP3 was performed. Results: All patients had presented with clinically evident maculopathy and visual acuities in the range of 1/50 Metervisus to 0.8 p [dec.]. All had specific electroretinogrammes. All PRPH2 mutations were autosomal dominant. One family was heterozygous for a previously reported missense mutation in the PRPH2 gene c.514C>T, p.R172W. The other patient was heterozygous for a so far non-described PRPH2 deletion and frameshift mutation c.74_77delGGTT, p.W25SfsX12 leading most likely to a truncated, dysfunctional protein. All patients showed a significant, inter-individual phenotypical variability. Conclusion: The data add to the documented phenotypical variability of PRPH2 mutations and describe the c.74_77delGGTT, p.W25SfsX12 mutation within PRPH2 for the first time. FAF, OCT and electrophysiological exams are helpful tools for diagnosis and evaluation of macular disease due to PRPH2 mutations.

Schlüsselwörter

PRPH2/RDS - Elektrophysiologie - Genotyp-Phänotyp-Korrelation - Molekulargenetik - Makuladystrophie

Key words

PRPH2/RDS - electrophysiology - genotype-phenotype correlation - molecular genetics - macular dystrophy

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