ABSTRACT
OBJECTIVE: To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP). METHODS: Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment. RESULTS: In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carried the p.M390R variant. In addition, this variant was detected homozygously in 10 RP patients and 1 control, compound heterozygously in 3 patients, and heterozygously in 5 patients and 6 controls. The 14 patients with 2 BBS1 variants showed the entire clinical spectrum, from nonsyndromic RP to full-blown BBS. In 8 of 14 patients, visual acuity was significantly reduced. In patients with electroretinographic responses, a rod-cone pattern of photoreceptor degeneration was observed. CONCLUSIONS: Variants in BBS1 are significantly associated with nonsyndromic autosomal recessive RP and relatively mild forms of BBS. As exemplified in this study by the identification of a homozygous p.M390R variant in a control individual and in unaffected parents of BBS patients in other studies, cis - or trans -acting modifiers may influence the disease phenotype. CLINICAL RELEVANCE: It is important to monitor patients with an early diagnosis of mild BBS phenotypes for possible life-threatening conditions.
Subject(s)
Bardet-Biedl Syndrome/genetics , DNA/genetics , Microtubule-Associated Proteins/genetics , Mutation, Missense , Retinitis Pigmentosa/genetics , Adult , Alleles , Bardet-Biedl Syndrome/diagnosis , Bardet-Biedl Syndrome/ethnology , Canada/epidemiology , DNA Mutational Analysis , Electroretinography , Ethnicity , Europe/epidemiology , Female , Humans , Israel/epidemiology , Male , Microscopy, Acoustic , Microtubule-Associated Proteins/metabolism , Middle Aged , Ophthalmoscopy , Pedigree , Phenotype , Prevalence , Retinitis Pigmentosa/diagnosis , Retinitis Pigmentosa/ethnologyABSTRACT
PURPOSE: Leber congenital amaurosis (LCA) is genetically heterogeneous, with 15 genes identified thus far, accounting for â¼70% of LCA patients. The aim of the present study was to identify new genetic causes of LCA. METHODS: Homozygosity mapping in >150 LCA patients of worldwide origin was performed with high-density SNP microarrays to identify new disease-causing genes. RESULTS: In three isolated LCA patients, the authors identified large homozygous regions on chromosome 3 encompassing the IQCB1 gene, which has been associated with Senior-Loken syndrome (SLSN), characterized by nephronophthisis and retinal degeneration. Mutation analysis of IQCB1 in these three patients and a subsequent cohort of 222 additional LCA patients identified frameshift and nonsense mutations in 11 patients diagnosed with LCA. On re-inspection of the patient's disease status, seven were found to have developed SLSN, but four maintained the diagnosis of LCA as the kidney function remained normal. CONCLUSIONS: Results show that the onset of renal failure in patients with IQCB1 mutations is highly variable, and that mutations are also found in LCA patients without nephronophthisis, rendering IQCB1 a new gene for LCA. However, these patients are at high risk for developing renal failure, which in early stages is often not recognized and can cause sudden death from fluid and electrolyte imbalance. It is therefore recommended that all LCA patients be screened for IQCB1 mutations, to follow them more closely for kidney disease.