The adaptive functioning profile of Pitt-Hopkins syndrome.

BACKGROUND: There are few cohort studies describing the adaptive functioning profile for Pitt-Hopkins syndrome (PTHS). In this study we examine the adaptive functioning profile for PTHS and compare it to Angelman syndrome (AS). METHOD: Caregivers of 14 individuals with PTHS, 33 with deletion AS and 23 with non-deletion AS, completed the Vineland Adaptive Behavior Scales-II. RESULTS: The profile of adaptive functioning in PTHS was characterised by strengths in socialisation, followed by motor skills, communication then daily living skills. The PTHS group scored significantly lower than the non-deletion AS group on all domains except socialisation and significantly lower than the deletion AS group, for motor skills only. CONCLUSIONS: An uneven adaptive behavior profile for individuals with PTHS mirrors that of AS, with implications for assessment and intervention.

Inhibitory effects of pectenotoxins from marine algae on the polymerization of various actin isoforms.

Pectenotoxins (PTXs) are marine toxins produced by dinoflagellates and which accumulate in shellfish. There are at least 14 different analogs of PTX with slight variations in structure leading to different chemical properties and consequently different toxicities. Since preliminary studies have shown that the parent compound PTX1 targets actin, we investigated the effects of two analogs, PTX2 and PTX2 seco acid, on the polymerization and depolymerization of skeletal muscle actin, smooth muscle actin, cardiac muscle actin, and non-muscle actin. Optimized actin assays using fluorescently labeled skeletal muscle actin and SDS-PAGE were jointly used to determine the relative amounts of filamentous and globular actin formed during polymerization and depolymerization experiments. Our findings suggest that PTX2 causes a dose-dependent decrease in both the rate and yield of skeletal muscle actin polymerization (IC50 values of 44 and 177 nM; respectively), with no significant effects on depolymerization. Moreover, the inhibitory effects of PTX2 are conserved towards other actin isoforms (i.e., smooth muscle, cardiac muscle, and non-muscle), as the inhibitory effects on actin polymerization were also observed with similar IC50 values (range: 19-94 nM). No inhibitory effects on polymerization were observed for PTX2 seco acid, suggesting an intact lactone ring is necessary for bioactivity.

The gene for the muted (mu) mouse, a model for Hermansky-Pudlak syndrome, defines a novel protein which regulates vesicle trafficking.

The muted (mu) mouse is a model for Hermansky-Pudlak Syndrome (HPS), an inherited disorder of humans causing hypopigmentation, hemorrhaging and early death due to lung abnormalities. The mu gene regulates the synthesis of specialized mammalian organelles such as melanosomes, platelet dense granules and lysosomes. Further, balance defects indicate that it controls the synthesis of otoliths of the inner ear. The mu gene has been identified by a positional/candidate approach involving large mouse interspecific backcrosses. It encodes a novel ubiquitously expressed transcript, specifying a predicted 185 amino acid protein, whose expression is abrogated in the mu allele which contains an insertion of an early transposon (ETn) retrotransposon. Expression is likewise expected to be lost in the mu( J) allele which contains a deletion of a single base pair within the coding region. The presence of structurally aberrant melanosomes within the eyes of mutant mice together with localization of the muted protein within vesicles in both the cell body and dendrites of transfected melan-a melanocytes emphasizes the role of the mu gene in vesicle trafficking. The mu gene is present only in mice and humans among analyzed genomes. As is true for several other recently identified mouse HPS genes, the mu gene is absent in lower eukaryotes. Therefore, the mu gene is a member of the novel gene set that has evolved in higher eukaryotes to regulate the synthesis/function of highly specialized subcellular organelles such as melanosomes and platelet dense granules.

Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene.

Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding and pulmonary fibrosis result from defects of melanosomes, platelet dense granules and lysosomes. HPS is common in Puerto Rico, where it is caused by mutations in the genes HPS1 and, less often, HPS3 (ref. 8). In contrast, only half of non-Puerto Rican individuals with HPS have mutations in HPS1 (ref. 9), and very few in HPS3 (ref. 10). In the mouse, more than 15 loci manifest mutant phenotypes similar to human HPS, including pale ear (ep), the mouse homolog of HPS1 (refs 13,14). Mouse ep has a phenotype identical to another mutant, light ear (le), which suggests that the human homolog of le is a possible human HPS locus. We have identified and found mutations of the human le homolog, HPS4, in a number of non-Puerto Rican individuals with HPS, establishing HPS4 as an important HPS locus in humans. In addition to their identical phenotypes, le and ep mutant mice have identical abnormalities of melanosomes, and in transfected melanoma cells the HPS4 and HPS1 proteins partially co-localize in vesicles of the cell body. In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggest that the HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis.