Open Access Highly Accessed Open Badges Research

The ADAMTS18 gene is responsible for autosomal recessive early onset severe retinal dystrophy

Ivana Peluso1, Ivan Conte1, Francesco Testa2, Gopuraja Dharmalingam1, Mariateresa Pizzo1, Rob WJ Collin3, Nicola Meola1, Sara Barbato1, Margherita Mutarelli1, Carmela Ziviello1, Anna Maria Barbarulo4, Vincenzo Nigro15, Mariarosa AB Melone46, the European Retinal Disease Consortium, Francesca Simonelli2 and Sandro Banfi15*

Author Affiliations

1 Telethon Institute of Genetics and Medicine, via Pietro Castellino,111, Naples 80131, Italy

2 Department of Ophthalmology, Second University of Naples, Naples, Italy

3 Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

4 First Neurological Clinic, Department of Clinical and Experimental Medicine and Surgery, Naples, Italy

5 Medical Genetics, Department of Biochemistry, Biophysics and General Pathology, Second University of Naples; Telethon Institute of Genetics and Medicine, via Pietro Castellino, 111, Naples 80131, Italy

6 Institute of Biochemistry of Protein (IBP), CNR, Naples, Italy

For all author emails, please log on.

Orphanet Journal of Rare Diseases 2013, 8:16  doi:10.1186/1750-1172-8-16

Published: 28 January 2013



Inherited retinal dystrophies, including Retinitis Pigmentosa and Leber Congenital Amaurosis among others, are a group of genetically heterogeneous disorders that lead to variable degrees of visual deficits. They can be caused by mutations in over 100 genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying a novel gene for an autosomal recessive form of early onset severe retinal dystrophy in a patient carrying no previously described mutations in known genes.


An integrated strategy including homozygosity mapping and whole exome sequencing was used to identify the responsible mutation. Functional tests were performed in the medaka fish (Oryzias latipes) model organism to gain further insight into the pathogenic role of the ADAMTS18 gene in eye and central nervous system (CNS) dysfunction.


This study identified, in the analyzed patient, a homozygous missense mutation in the ADAMTS18 gene, which was recently linked to Knobloch syndrome, a rare developmental disorder that affects the eye and the occipital skull. In vivo gene knockdown performed in medaka fish confirmed both that the mutation has a pathogenic role and that the inactivation of this gene has a deleterious effect on photoreceptor cell function.


This study reveals that mutations in the ADAMTS18 gene can cause a broad phenotypic spectrum of eye disorders and contribute to shed further light on the complexity of retinal diseases.

Inherited retinal dystrophies; ADAMTS18; Exome; Homozygosity mapping; Medaka fish; Knobloch syndrome