Abstract
Purpose: :
Cone (CD) and cone-rod dystrophies (CRD) are characterized by decreased visual acuity, color vision deficiency and photophobia, and in case of CRD by progressive loss in peripheral vision and night blindness. CD and CRD can be inherited as an autosomal recessive, autosomal dominant (ad) and X-linked trait. To date ten genes have been associated with the rare autosomal dominant forms of adCD and adCRD. In some instances only a single report describing mutation(s) in the respective gene has been published. Since systematic investigations for these genes in patients with adCD and adCRD are lacking, 51 unrelated patients and families with this rare diagnosis were collected and analyzed to determine the prevalence and mutation spectrum of PRPH2, CRX, GUCA1A, GUCY2D, AIPL1 and UNC119 gene mutations in this cohort. PITPNM3 had already been excluded in an earlier collaboration project.
Methods: :
Mutation screening and segregation analysis was performed by DNA sequencing of PCR amplified genomic DNA applying BigDye sequencing chemistry (Applied Biosystems, Darmstadt, Germany), except for mutation scanning in GUCY2D which was performed by PCR/RFLP analysis. Novel sequence variants were excluded in 100 healthy control individuals.
Results: :
We identified ten novel and five already published mutations in 24 families with adCD and adCRD: two independent patients and families carried mutations in CRX (4%), four in GUCA1A (8%), six in PRPH2 (12%) and twelve patients and families with adCD and adCRD were shown to have mutations in GUCY2D (24%). No pathogenic variants were identified in AIPL1 and UNC119.
Conclusions: :
Our analysis shows that mutations in the known genes account for 47% of all adCD and adCRD cases, while 53% remain unsolved giving evidence for further genetic heterogeneity. GUCY2D is the major gene for these disorders, followed by PRPH2, GUCA1A and CRX. Mutations in AIPL1, UNC119 and PITPNM3 seem to be rare causes of adCD and adCRD, and further studies are required to evaluate their contribution to these phenotypes.
Keywords: genetics • retinal degenerations: hereditary • gene screening