A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics

Abstract

An extended, highly consanguineous Israeli Bedouin family with at least 20 individuals exhibiting a unique phenotype of oculocutaneous albinism (OCA) was identified. All known OCA genes were excluded in this family. Electron microscopic analysis of platelets revealed absence of dense bodies, suggesting a diagnosis of Hermansky-Pudlak syndrome (HPS). HPS is a rare autosomal recessive disorder of lysosome-related organelle biogenesis, clinically characterized by OCA and platelet dysfunction, sometimes accompanied by other systemic pathologies. All human HPS genes (HPS1-8) and five genes corresponding to murine HPS models were evaluated. Haplotype analysis and homozygosity mapping of the HPS loci revealed linkage to chromosome 10 in the studied family. Subsequently, a novel insertion mutation, c.1066-1067insG was identified in HPS6. Most frameshift mutations generating premature termination codon cause mRNA nonsense mediated decay (NMD), while intronless genes like HPS6 are usually not monitored by NMD. Expression analysis revealed no mRNA decay in patient's fibroblasts, hence truncated protein is most probably produced. Confocal microscopy revealed abnormal distribution of LAMP-3 (lysosomal associated membrane protein-3) in fibroblasts from the patients, indicating abnormal trafficking of lysosomal lineage organelles. So far, a single HPS-6 patient phenotypically similar to HPS-3 and HPS-5 has been identified. The HPS-6 phenotype in the studied family is unique since it resembles OCA and not HPS. Therefore, our finding broadens the phenotypic definition of HPS. Two major genetic isolates of HPS-1 and HPS-3 patients were previously diagnosed in Puerto Rico. The extended Bedouin family is the largest isolate of non-Puerto Rican HPS patients.