Mutations in SAMD7 cause autosomal-recessive macular dystrophy with or without cone dysfunction

Miriam Bauwens; Elifnaz Celik; Dinah Zur; Siying Lin; Mathieu Quinodoz; Michel Michaelides; Andrew R Webster; Filip Van Den Broeck; Bart P Leroy; Leah Rizel; Abigail R Moye; Audrey Meunier; Hoai Viet Tran; Alexandre P Moulin; Quinten Mahieu; Mattias Van Heetvelde; Gavin Arno; Carlo Rivolta; Elfride De Baere; Tamar Ben-Yosef

doi:10.1016/j.ajhg.2024.01.001

Mutations in SAMD7 cause autosomal-recessive macular dystrophy with or without cone dysfunction

Am J Hum Genet. 2024 Feb 1;111(2):393-402. doi: 10.1016/j.ajhg.2024.01.001. Epub 2024 Jan 24.

Authors

Miriam Bauwens¹, Elifnaz Celik², Dinah Zur³, Siying Lin⁴, Mathieu Quinodoz⁵, Michel Michaelides⁴, Andrew R Webster⁴, Filip Van Den Broeck⁶, Bart P Leroy⁷, Leah Rizel⁸, Abigail R Moye², Audrey Meunier⁹, Hoai Viet Tran¹⁰, Alexandre P Moulin¹¹, Quinten Mahieu¹, Mattias Van Heetvelde¹, Gavin Arno¹², Carlo Rivolta⁵, Elfride De Baere¹, Tamar Ben-Yosef¹³

Affiliations

¹ Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
² Institute of Molecular and Clinical Ophthalmology Basel (IOB), 4031 Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, 4031 Basel, Switzerland.
³ Ophthalmology Division, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
⁴ National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and the Institute of Ophthalmology, London, UK; Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
⁵ Institute of Molecular and Clinical Ophthalmology Basel (IOB), 4031 Basel, Switzerland; Department of Ophthalmology, University Hospital Basel, 4031 Basel, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK.
⁶ Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Head & Skin, Ghent University, 9000 Ghent, Belgium.
⁷ Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium; Department of Head & Skin, Ghent University, 9000 Ghent, Belgium; Department of Ophthalmology, Ghent University Hospital, 9000 Ghent, Belgium; The Division of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ The Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
⁹ Department of Ophthalmology, Centre Hospitalier Universitaire Saint-Pierre, 1000 Brussels, Belgium.
¹⁰ Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, Switzerland; Centre for Gene Therapy and Regenerative Medicine, King's College London, London, UK.
¹¹ Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, Switzerland.
¹² National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and the Institute of Ophthalmology, London, UK; Institute of Ophthalmology, University College London, London EC1V 9EL, UK; North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3BH, UK.
¹³ The Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel. Electronic address: benyosef@technion.ac.il.

PMID: 38272031
PMCID: PMC10870129 (available on 2024-08-01)
DOI: 10.1016/j.ajhg.2024.01.001

Abstract

Sterile alpha motif domain containing 7 (SAMD7) is a component of the Polycomb repressive complex 1, which inhibits transcription of many genes, including those activated by the transcription factor Cone-Rod Homeobox (CRX). Here we report bi-allelic mutations in SAMD7 as a cause of autosomal-recessive macular dystrophy with or without cone dysfunction. Four of these mutations affect splicing, while another mutation is a missense variant that alters the repressive effect of SAMD7 on CRX-dependent promoter activity, as shown by in vitro assays. Immunostaining of human retinal sections revealed that SAMD7 is localized in the nuclei of both rods and cones, as well as in those of cells belonging to the inner nuclear layer. These results place SAMD7 as a gene crucial for human retinal function and demonstrate a significant difference in the role of SAMD7 between the human and the mouse retina.

Keywords: SAMD7; inherited retinal diseases; macular dystrophy; mutation; retina.

MeSH terms

Animals
Eye Abnormalities*
Homeodomain Proteins / genetics
Humans
Macular Degeneration* / genetics
Mice
Mutation / genetics
Retina
Trans-Activators / genetics

Substances

Trans-Activators
Homeodomain Proteins