Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder of oculocutaneous albinism and bleeding attributable to storage-pool-deficient platelets. Although at least 14 mouse models of HPS exist, the human disorders that comprise HPS, i.e., HPS-1, HPS-2, HPS-3, and HPS-4, are recognized to result from mutations in four genes, viz., HPS1, ADTB3A, HPS3, and HPS4, respectively. To characterize further the recently identified HPS-4 disease on molecular and clinical grounds, we first identified the genomic organization of HPS4, located on chromosome 22qll.2-ql2.2, including its intron/exon boundaries. We found that HPS4 produces at least two alternatively spliced mRNA transcripts that differ at their 5′-ends. Next, we performed an extensive analysis of 22 unassigned HPS patients (i.e., not having HPS-1, HPS-2, or HPS-3 disease). Using single-strand conformation polymorphism, we determined that seven of the 22 patients had HPS-4. In these seven individuals, we identified five different HPS4 mutations, including one frameshift insertion, one missense, and three nonsense mutations. Three alleles in two patients contained the previously reported Q698insAAGCA frameshift. Three HPS4 mutations were newly described. Four alleles in three patients contained R217X. and two siblings were compound heterozygotes for E138X and E222X. Clinically, our HPS-4 patients exhibited iris transillumination, variable hair and skin pigmentation, absent platelet dense bodies, and occasional pulmonary fibrosis and granulomatous colitis, a severe phenotype similar to that of patients with HPS-1.
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