Mutation Analysis of Patients with Hermansky-Pudlak Syndrome: A Frameshift Hot Spot in the HPS Gene and Apparent Locus Heterogeneity

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5' splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321-322. Overall, however, we detected mutations in the HPS gene in only about half of non-Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.

Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

“…No curative therapies exist. HPS is a genetically heterogenous disease and is found in diverse populations worldwide (Hazelwood et al, 1997;Oh et al, 1998;Shotelersuk and Gahl, 1998;Spritz, 1999;Dell'Angelica et al, 1999). This is consistent with the existence of at least 14 genetically distinct mouse pigment mutants that exhibit phenotypes similar to those of HPS patients (Swank et al, 1998;Swank et al, in press).…”

Hermansky–Pudlak Syndrome and Pale Ear: Melanosome‐Making for the Millennium

“…These (35)(36)(37) and other investigators (38) have described a total of 12 different pathological mutations of the HPS gene in patients from a variety of ethnic groups (Fig. 2).…”

“…No HPS mRNA is detectable from this mutant allele (39), indicating that HPS mRNA is subject to the so-called 'nonsense-mediated decay' of aberrantly-translated mRNAs. Most Puerto Rican HPS patients are homozygous for the codon 491-496 duplication (32,35,39), although HPS has not been reported elsewhere in the Caribbean, suggesting that this HPS gene mutant allele probably arose on or was introduced to the island of Puerto Rico early during its history and became frequent by chance and occult inbreeding; there is no evidence for any selective Pigment Cell Res. 13,2000 As shown in Table 1, mutations in a number of the other mouse HPS-like loci have also been found.…”

“…Moreover, genetic mapping studies of some of these patients and their families fail to support linkage to markers in 10q23 (35). Together, these data suggest that additional 'HPS' loci in the human genome remain to be discovered.…”

Hermansky-Pudlak Syndrome with a Novel Mutation

“…After the discovery of the location of the HPS1 gene on band 10q23, the other five subtypes [HPS2 (AP3B1), HPS3, HPS4, HPS5 and HPS6 (2-5)] have been reported. The incidence of HPS is frequent in Puerto Rico, however it is relatively rare in non-Puerto Rican countries (6). Patients with the HPS1 gene disorder frequently present with pulmonary fibrosis (7).…”