CHM gene molecular analysis and X‐chromosome inactivation pattern determination in two families with choroideremia

Abstract

Choroideremia is an X-linked recessive retinal dystrophy characterized by progressive loss of the photoreceptor, the retinal pigment epithelium, and the choriocapillaris layers which ultimately can result in blindness by the fifth decade of life. The disease is caused by mutations in the gene CHM, which encodes a protein involved in the regulation of intracellular vesicular traffic. Typically, hemizygous males are affected by the disease and female carriers are asymptomatic with only a diffuse mottled pattern of hyperpigmentation on funduscopy. Uncommon instances of fully affected females have been described previously and these cases are proposed to arise from an skewed Lyonization mechanism preferentially inactivating the X chromosome carrying the normal CHM allele. In this work, the clinical and molecular features of two Mexican families with choroideremia are described. A novel and a previously described CHM mutation were identified. X-chromosome inactivation assays were performed in a total of 12 heterozygous carriers from the two families. In an affected female from family A, a random X-inactivation pattern was demonstrated; on the other hand, in a female carrier from family B displaying a conspicuous pattern of pigment epithelium mottling at the peripheral retina, a skewed X-inactivation pattern was found. However, the X-chromosome preferentially inactivated in this female was the one carrying the mutated allele. Our results add to the genotypic spectrum in choroideremia and does not support a correlation between X-inactivation status and abnormal retinal phenotype in heterozygous female carriers from these two families.

AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models

“…Since the CHM locus is on the X-chromosome, choroideremia is typically only diagnosed in males. Although female carriers of the disease are usually asymptomatic, retinal exams often reveal a patchy degeneration of the retina and RPE and female individuals can be affected depending on the extent of X-inactivation of the normal X chromosome (lyonization) [7], [8].…”

The Role of X-Chromosome Inactivation in Retinal Development and Disease

“…All carriers had patches of pigmentary retina changes on fundoscopic exam, although these patches did not always correlate with areas of reduced function on mfERG. In two families with X-linked choroideremia, no link was found between female carrier phenotype and XCI skewing in peripheral blood (Perez-Cano et al 2009). …”

Vi-2 : Apport De l'ÉLECTROPHYSIOLOGIE Chez l'ADULTE : Exemples

“…L'évolution se fait souvent vers une atteinte importante du champ visuel périphérique aux environs de la cinquième décennie [Perez-Cano et al, 2009] avec cependant une vision centrale qui reste longtemps préservée [MacDonald et al, 2008]. Des mutations dans le gène CHM sont à l'origine de la déficience de la protéine REP1 (Rab escort protein 1) [MacDonald et al, 2009], [Perez-Cano, et al, 2009] qui est responsable du transport vésiculaire intracellulaire [Seabra et al, 2002], , [Preising, Ayuso, 2004], [Tolmachova et al, 2006].…”