CHM – Choroideremia

Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by loss-of-function mutations in CHM, which encodes Rab escort protein-1 (REP1). Affected hemizygous males exhibit early nyctalopia and progressive peripheral visual field constriction, culminating in central vision loss, while female carriers display variable fundus changes due to random X-inactivation. REP1 is essential for prenylation of Rab GTPases and intracellular vesicular trafficking in retinal pigment epithelium and photoreceptors.

Genetic studies in diverse populations have identified over 106 unique pathogenic CHM variants, predominantly nonsense, frameshift, splice site, and large deletions leading to REP1 deficiency. In one large cohort of 128 unrelated affected males, mutation screening revealed a broad mutational spectrum without hot spots, and segregation of variants in multiple pedigrees confirmed X-linked inheritance ([PMID:27247961]). Further analysis of 57 families demonstrated mutations in 54, reinforcing the high detection rate across ethnically varied cohorts ([PMID:12203991]).

Variant spectrum includes c.757C>T (p.Arg253Ter) and c.799C>T (p.Arg267Ter) among recurrent stop-gain mutations, as well as splice-site errors and deep-intronic insertions. In the Survey of Ophthalmology case series, c.757C>T (p.Arg253Ter) co-segregated with choroideremia in seven affected male relatives ([PMID:19422966]; [PMID:22965595]), exemplifying genotype–phenotype concordance.

Functional assays in patient-derived cells and animal models demonstrate absence of REP1 protein, accumulation of unprenylated Rab substrates, and ultrastructural choroidal melanosome defects. Restoration of REP1 expression via AAV-mediated CHM delivery in iPSC-derived RPE rescues prenylation deficits, validating the loss-of-function mechanism and supporting gene replacement strategies ([PMID:28911202]).

Clinically, affected males present in the first decade with night blindness (HP:0007675) and peripheral visual field loss (HP:0001133), progressing at variable rates. Female carriers may develop symptomatic retinal dystrophy later in life, highlighting the need for molecular confirmation and surveillance.

Taken together, the CHM–choroideremia association is definitive, with extensive genetic and experimental evidence guiding accurate diagnosis, genetic counseling, and patient selection for emerging gene therapy trials. Key take-home: molecular testing for CHM loss-of-function variants is essential for early diagnosis and qualification for gene replacement therapy.

References

• Molecular genetics & genomic medicine • 2016 • Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy PMID:27247961
• Human Mutation • 2002 • Mutational analysis of patients with the diagnosis of choroideremia PMID:12203991
• Survey of ophthalmology • 2009 • Choroideremia: new findings from ocular pathology and review of recent literature PMID:19422966
• Archives of ophthalmology • 2012 • Clinical characteristics of a large choroideremia pedigree carrying a novel CHM mutation PMID:22965595
• Human molecular genetics • 2017 • Pathogenicity of a novel missense variant associated with choroideremia and its impact on gene replacement therapy PMID:28911202

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