Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defective lysosome-related organelles. Here, we report the identification of two HPS patients with mutations in the beta 3A subunit of the heterotetrameric AP-3 complex. The patients' fibroblasts exhibit drastically reduced levels of AP-3 due to enhanced degradation of mutant beta 3A. The AP-3 deficiency results in increased surface expression of the lysosomal membrane proteins CD63, lamp-1, and lamp-2, but not of nonlysosomal proteins. These differential effects are consistent with the preferential interaction of the AP-3 mu 3A subunit with tyrosine-based signals involved in lysosomal targeting. Our results suggest that AP-3 functions in protein sorting to lysosomes and provide an example of a human disease in which altered trafficking of integral membrane proteins is due to mutations in a component of the sorting machinery.

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.

Summary Purpose:  Previous studies found a strong association between HLA‐B*1502 and carbamazepine (CBZ)‐induced Stevens‐Johnson syndrome (SJS) in Han Chinese, but not in Caucasian populations. Even in Han Chinese, the HLA‐B*1502 was not associated with CBZ‐induced maculopapular eruptions (MPE). This study seeks to identify whether HLA‐B*1502 is associated with CBZ‐ or phenytoin (PHT)‐induced SJS or MPE in a Thai population. Methods:  Eighty‐one Thai epileptic patients between 1994 and 2007 from the Chulalongkorn Comprehensive Epilepsy Program were recruited. Thirty‐one subjects had antiepileptic drug (AED)‐induced SJS or MPE (6 CBZ‐SJS, 4 PHT‐SJS, 9 CBZ‐MPE, 12 PHT‐MPE), and 50 were AED‐tolerant controls. Results:  For the first time, a strong association between HLA‐B*1502 and PHT‐induced SJS was found (p = 0.005). A strong association was also found between the HLA‐B*1502 and CBZ‐induced SJS (p = 0.0005), making Thai the first non‐Chinese population demonstrating such an association. Some patients, who were HLA‐B*1502 and suffered from CBZ‐induced SJS, could be tolerant to PHT and vice versa. This suggests that HLA‐B*1502 may be a common attribute required for a Thai patient to develop SJS from these two AEDs; other different elements, however, are also needed for each AED. In addition, no association between HLA‐B alleles and CBZ‐ or PHT‐induced MPE was found. Conclusions:  CBZ‐ and PHT‐induced SJS, but not MPE, is associated with HLA‐B*1502 allele in Thai population.

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.