ABSTRACT
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.
Subject(s)
Abnormalities, Multiple/genetics , Hermanski-Pudlak Syndrome/genetics , Membrane Proteins/genetics , Adult , Alternative Splicing , Base Sequence , DNA Mutational Analysis , Female , Hermanski-Pudlak Syndrome/diagnosis , Humans , Male , Molecular Sequence Data , Mutation, Missense , Puerto Rico , Young AdultABSTRACT
BACKGROUND: In the last decade, Hermansky-Pudlak syndrome (HPS) has arisen as an instructive disorder for cell biologists to study the biogenesis of lysosome related organelles (LROs). Of the eight human HPS subtypes, only subtypes 1 through 5 are well described. AIM: To characterise extensively the HPS-6 subtype, caused by defects in HPS6, a subunit of the biogenesis of lysosome related organelles complex-2 (BLOC-2). METHODS: Mutation analysis for the HPS6 gene was performed on DNA from our group of unclassified HPS patients. The clinical phenotype of patients with HPS6 mutations was then carefully ascertained, and their cultured dermal melanocytes were employed for cellular immunofluorescence studies. RESULTS: Molecular studies showed a variety of mutations in the single exon HPS6 gene, including frame shift, missense, and nonsense mutations as well as a approximately 20 kb deletion spanning the entire HPS6 genomic region. Cellular studies revealed that the melanogenic proteins tyrosinase and tyrosinase related protein 1 failed to be efficiently delivered to the melanosomes of HPS-6 patients, explaining their hypopigmentation. Clinical studies indicated that HPS-6 patients exhibit oculocutaneous albinism and a bleeding diathesis. Importantly, granulomatous colitis and pulmonary fibrosis, debilitating features present in HPS subtypes 1 and 4, were not detected in our HPS-6 patients. CONCLUSION: The HPS-6 subtype resembles other BLOC-2 defective subtypes (that is, HPS-3 and HPS-5) in its molecular, cellular and clinical findings. These findings are not only important for providing a prognosis to newly diagnosed HPS-6 patients, but also for further elucidation of HPS function in the biogenesis of LROs.
Subject(s)
Hermanski-Pudlak Syndrome/genetics , Hermanski-Pudlak Syndrome/pathology , Intracellular Signaling Peptides and Proteins/genetics , Adolescent , Adult , Amino Acid Sequence , Base Sequence , Blotting, Northern , DNA/chemistry , DNA/genetics , Female , Genetic Variation , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins/metabolism , Male , Melanosomes/genetics , Melanosomes/pathology , Middle Aged , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Young AdultABSTRACT
The purpose of this experimental study was to determine the effectiveness of teaching primiparous mothers about infant behavior. Experimental mothers (n = 17) received a teaching intervention representative of the Brazelton Neonatal Behavioral Assessment Scale when their infants were 2 weeks old; contrast mothers (n = 16) completed a Newborn Information Checklist about infant behavior at home two weeks postnatally; control mothers (n = 13) received neither teaching nor a checklist. At a 4-week postnatal office visit, experimental mothers had more knowledge about infant behavior than either the contrast or control mothers. There was no difference among the groups regarding maternal confidence in interpreting behavioral cues of their own infant. Contrast mothers reported wanting information about topics included in the teaching intervention.
