CHM mutation spectrum and disease: An update at the time of human therapeutic trials

Abstract

Choroideremia is an X‐linked inherited retinal disorder (IRD) characterized by the degeneration of retinal pigment epithelium, photoreceptors, choriocapillaris and choroid affecting males with variable phenotypes in female carriers. Unlike other IRD, characterized by a large clinical and genetic heterogeneity, choroideremia shows a specific phenotype with causative mutations in only one gene, CHM. Ongoing gene replacement trials raise further interests in this disorder. We describe here the clinical and genetic data from a French cohort of 45 families, 25 of which carry novel variants, in the context of 822 previously reported choroideremia families. Most of the variants represent loss‐of‐function mutations with eleven families having large (i.e. ≥6 kb) genomic deletions, 18 small insertions, deletions or insertion deletions, six showing nonsense variants, eight splice site variants and two missense variants likely to affect splicing. Similarly, 822 previously published families carry mostly loss‐of‐function variants. Recurrent variants are observed worldwide, some of which linked to a common ancestor, others arisen independently in specific CHM regions prone to mutations. Since all exons of CHM may harbor variants, Sanger sequencing combined with quantitative polymerase chain reaction or multiplex ligation‐dependent probe amplification experiments are efficient to achieve the molecular diagnosis in patients with typical choroideremia features.

Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription

“…Pathogenic variants in the CHM gene result in complete loss of REP1, which is a typical feature of CHM cells [10,[16][17][18][19]. Genomic deletions involving CHM are loss-of-function defects that have been detected in about 15-20% of CHM patients [19][20][21][22][23]. Here, we report molecular characterization of seven large deletions that remove in part or all the CHM gene in Italian patients with choroideremia (Table 1).…”

“…Pathogenic variants in the CHM gene result in complete loss of REP1, which is a typical feature of CHM cells [10,[16][17][18][19]. Genomic deletions involving CHM are loss-of-function defects that have been detected in about 15-20% of CHM patients [19][20][21][22][23].…”

“…More than 420 unique CHM pathogenic sequence variants that often abolish REP1 synthesis have been identified in CHM patients (Leiden Open Variant Database-LOVD, https: //databases.lovd.nl/shared/genes/CHM; Human gene mutation database, HGMD ® , accessed on 16 July 2021) [16][17][18][19]. About 20% of patients have chromosomal deletions of variable size that remove single CHM exons or eliminate CHM and various contiguous genes [19]. No apparent correlation has been found between the size of the deletion and the severity of CHM, however, a few patients with deletions ranging between 5 and 12 Mb had syndromic CHM [20][21][22][23][24].…”

A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report

“…Adolescent affected males develop night blindness, which is followed by a gradual loss of peripheral vision between the second and third decades of life and complete blindness in the later stages of disease [ 2 ]. Female CHM mutation carriers are mainly asymptomatic or mildly symptomatic [ 3 ], and only a minority of cases present a severe phenotype, consisting of retinal and choroidal atrophy such as that observed in affected males [ 4 ].…”

“…CHM contains 15 exons and is expressed in many tissues, including brain, spleen, endocrine tissues and eye, with the highest levels of transcription shown in the retina, choroid and RPE [ 3 ]. CHM codes for the Rab Escort protein 1 (REP1) [ 2 ], which plays a key role in the cytosolic prenylation (i.e., the addition of geranylgeranyl groups) to the Rab GTPases, allowing prenylated Rabs to anchor to the membrane of intracellular organelles and vesicles [ 5 ].…”