title: A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8).
abstract: Hermansky-Pudlak syndrome (HPS) is genetically heterogeneous, and mutations in seven genes have been reported to cause HPS. Autozygosity mapping studies were undertaken in a large consanguineous family with HPS. Affected individuals displayed features of incomplete oculocutaneous albinism and platelet dysfunction. Skin biopsy demonstrated abnormal aggregates of melanosomes within basal epidermal keratinocytes. A homozygous germline frameshift mutation in BLOC1S3 (p.Gln150ArgfsX75) was identified in all affected individuals. BLOC1S3 mutations have not been previously described in patients with HPS, but BLOC1S3 encodes a subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Mutations in other BLOC-1 subunits have been associated with an HPS phenotype in humans and/or mouse, and a nonsense mutation in the murine orthologue of BLOC1S3 causes the reduced pigmentation (rp) model of HPS. Interestingly, eye pigment formation is reported to be normal in rp, but we found visual defects (nystagmus, iris transilluminancy, foveal hypoplasia, reduced visual acuity, and evidence of optic pathway misrouting) in affected individuals. These findings define a novel form of human HPS (HPS8) and extend genotype-phenotype correlations in HPS.
authors.affiliation: Section of Medical and Molecular Genetics, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, United Kingdom.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.forename: Shanaz
authors.initials: S
authors.lastname: Pasha
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: John R
authors.initials: JR
authors.lastname: Ainsworth
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Eady
authors.forename: Ban
authors.initials: B
authors.lastname: Dawood
authors.forename: Carole
authors.initials: C
authors.lastname: McKeown
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wilde
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D004817:Epidermis / Q000648:ultrastructure; D005123:Eye / Q000473:pathology; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D020411:Oligonucleotide Array Sequence Analysis; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D010974:Platelet Aggregation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: C509457:BLOC1S3 protein, human; D002352:Carrier Proteins; D000255:Adenosine Triphosphate