Institute for Ophtalmic Research, Centre for Ophtalmology, University of Tübingen, Tübingen, Germany.
Department of Ophtamology and Optometry, Medical University of Vienna, Vienna, Austria.
Molecular Genetics Laboratory, Institute for Ophtalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
Praxis für Humangenetik Tübingen & CeGaT GmbH, Tübingen, Tübingen, Germany.
Institut de La Vision. INSERM Paris, France.
Werner Reichardt Center for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
Mutations in the retinitis pigmentosa-1-like-1 (RP1L1) gene are the major cause of autosomal dominant occult macular dystrophy (OCMD), while recessive mutations have been linked to autosomal recessive retinitis pigmentosa (arRP). We present the clinical phenotype of a large German OCMD cohort, as well as four RP patients.
A total of 42 OCMD patients (27 families) and 4 arRP patients (3 families) with genetically confirmed mutations in RP1L1 were included. Genomic DNA was analyzed by targeted analysis of the c.133C>T;p.R45W mutation for all RP or macular dystrophy-related genes. All patients underwent ophthalmologic examination including psychophysical tests, electrophysiology, fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT). Follow-up time was up to 12 years.
In 25 OCMD index patients genomic testing revealed the heterozygous mutation c.133C>T;p.R45W in RP1L1; one patient was homozygous for the mutation. Two OCMD patients displayed the variants c.3599G>A;p.G1200D and c.2849G>A;p.R950H, respectively, in a heterozygous state. All OCMD patients showed characteristic clinical findings and typical microstructural photoreceptor changes. Two arRP patients displayed the novel homozygous mutations c.3022C>T;p.Q1008* and c.1107G>A;p.W369*, respectively, while two RP-siblings carried the two heterozygous mutations c.455G>A;p.R152Q and c.5959C>T;p.Q1987*, the first also being novel. All arRP cases were mild with disease onset ≈30 years and preserved ERG-responses.
OCMD phenotype showed consistent clinical findings including classical microstructural changes on SD-OCT. An important hallmark of RP1L1-related OCMD is the dominant family history with reduced penetrance. Furthermore, novel mutations in association with arRP were identified, outlining the complexity of the protein.