Novel mutations in the HPS1 gene among Puerto Rican patients.

Hermansky-Pudlak syndrome (HPS) is a disorder of oculocutaneous albinism (OCA) and platelet storage pool deficiency. Eight different disease-causing genes have been identified, whose gene products are thought to be involved in the biogenesis of lysosome-related organelles. HPS type 1 (HPS-1) is the most common HPS subtype in Puerto Rico, with a frequency of 1:1800 in the northwest of the island due to a founder mutation, i.e. a 16-bp duplication in exon 15 of the HPS1 gene (c.1472_1487dup16; p.H497QfsX90). We identified three Puerto Rican HPS-1 patients who carried compound heterozygous HPS1 mutations. One patient was heterozygous for c.937G>A, causing a missense mutation (p.G313S) at the 3 splice junction of exon 10. This mutation resulted in activation of a cryptic intronic splice site causing an aberrantly spliced HPS1 mRNA that included 144-bp of intronic sequence, producing 11 novel amino acids followed by a stop codon. The other two patients were heterozygous for the previously reported c.972delC in HPS1, resulting in a frameshift and a premature stop codon (p.M325WfsX6). These findings indicate that, among Puerto Ricans, other HPS1 mutations apart from the 16-bp duplication should be considered in the analysis of this population.

Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency.

Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G-->A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G-->A mutation and for either an 1831+2T-->G or a 2621-2A-->G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G-->A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G-->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.

Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies. Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease. HPS occurs with a frequency of one in 1800 in north-west Puerto Rico due to a founder effect. Several non-Puerto Rican patients also have mutations in HPS1, which produces a protein of unknown function. Another gene, ADTB3A, causes HPS in the pearl mouse and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle formation, implicating HPS as a disorder of membrane trafficking. We sought to identify other HPS-causing genes. Using homozygosity mapping on pooled DNA of 6 families from central Puerto Rico, we localized a new HPS susceptibility gene to a 1.6-cM interval on chromosome 3q24. The gene, HPS3, has 17 exons, and a putative 113.7-kD product expected to reveal how new vesicles form in specialized cells. The homozygous, disease-causing mutation is a large deletion and represents the second example of a founder mutation causing HPS on the small island of Puerto Rico. We also present an allele-specific assay for diagnosing individuals heterozygous or homozygous for this mutation.

Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome).

BACKGROUND: Hermansky-Pudlak syndrome is characterized by oculocutaneous albinism, a storage-pool deficiency, and lysosomal accumulation of ceroid lipofuscin, which causes pulmonary fibrosis and granulomatous colitis in some cases. All identified affected patients in northwest Puerto Rico are homozygous for a 16-bp duplication in exon 15 of a recently cloned gene, HPS. We compared the clinical and laboratory characteristics of these patients with those of patients without the 16-bp duplication. METHODS: Forty-nine patients -- 27 Puerto Ricans and 22 patients from the mainland United States who were not of Puerto Rican descent -- were given a diagnosis on the basis of albinism and the absence of platelet dense bodies. We used the polymerase chain reaction to determine which patients carried the 16-bp duplication. RESULTS: Twenty-five of the Puerto Rican patients were homozygous for the 16-bp duplication, whereas none of the non-Puerto Rican patients carried this mutation. Like the patients without the duplication, the patients with the 16-bp duplication had a broad variation in pigmentation. Nine of 16 adults with the duplication, but none of the 10 without it, had a diffusing capacity for carbon monoxide that was less than 80 percent of the predicted value. High-resolution computed tomography in 12 patients with the 16-bp duplication revealed minimal fibrosis in 8, moderate fibrosis in 1, severe fibrosis in 1, and no fibrosis in 2. Computed tomography in eight patients without the duplication revealed minimal fibrosis in three and no fibrosis in the rest. Inflammatory bowel disease developed in eight patients (four in each group) between 3 and 25 years of age. CONCLUSIONS: The 16-bp duplication in exon 15 of HPS, which we found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults.

Evidence for locus heterogeneity in Puerto Ricans with Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) consists of ocu-locutaneous albinism, a platelet storage-pool deficiency, and ceroid lipofuscinosis. In a recent report on the cloning of an HPS gene, all 22 Puerto Rican HPS patients were homozygous for a 16-bp duplication in exon 15. This presumably reflected a founder effect for the HPS mutation in Puerto Rico. Nevertheless, we ascertained two individuals from central Puerto Rico who lacked the 16-bp duplication, exhibited significant amounts of normal-size HPS mRNA by northern blot analysis, and had haplotypes in the HPS region that were different from the haplotype of every 16-bp-duplication patient. Moreover, these two individuals displayed no mutations in their cDNA sequences, throughout the entire HPS gene. Both patients exhibited pigment dilution, impaired visual acuity, nystagmus, a bleeding diathesis, and absent platelet dense bodies, confirming the diagnosis of HPS. These findings indicate that analysis of Puerto Rican patients for the 16-bp duplication in HPS cannot exclude the diagnosis of HPS. In addition, HPS most likely displays locus heterogeneity, consistent with the existence of several mouse strains manifesting both pigment dilution and a platelet storage-pool deficiency.

Effect of growth hormone treatment on serum creatinine concentration in patients with cystinosis and chronic renal disease.

Three patients with nephropathic cystinosis and chronic renal disease, treated since early childhood with orally administered cysteamine, had an accelerated rate of rise of serum creatinine values after receiving recombinant human growth hormone. During 18 to 24 months of growth hormone treatment, each patient had a twofold to fourfold increase in growth velocity. The slope of the plot of reciprocal serum creatinine values versus age for each patient after growth hormone treatment was significantly steeper than the pretreatment slope. Growth hormone treatment had no effect on the rate of change of the uncorrected 24-hour renal creatinine clearance. We conclude that these patients gained body size but failed to compensate for their increased creatinine production with an increase in glomerular filtration rate. The result was an accelerated rate of rise of their serum creatinine values, hastening renal transplantation in one patient and the anticipated need for transplantation in another.

Course of nephropathic cystinosis after age 10 years.

We identified 80 patients with nephropathic cystinosis older than age 10 years in the United States and Canada. The oldest reported individual was 26 years of age. Ninety percent of patients had received at least one renal allograft. Age at the time of first transplant varied between 7 and 17 years (mean 10.0 years). Almost three fourths of the patients required thyroid replacement, 27% had splenomegaly, and 42% had hepatomegaly. Photophobia was noted in 86% of patients, decreased visual acuity in 32%, and corneal ulcerations in 15%. Neurologic involvement, renal osteodystrophy, and diabetes mellitus were unusual. All these late complications of nephropathic cystinosis contribute to a description of the natural history of the disease and provide a rationale for the therapeutic use of cystine-depleting agents after renal transplantation.