A BLOC-1 mutation screen reveals a novel BLOC1S3 mutation in Hermansky-Pudlak Syndrome type 8.
Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous disorder of lysosome-related organelle biogenesis and is characterized by oculocutaneous albinism and a bleeding diathesis. Over the past decade, we screened 250 patients with HPS-like symptoms for mutations in the genes responsible for HPS subtypes 1-6. We identified 38 individuals with no functional mutations, and therefore, we analyzed all eight genes encoding the biogenesis of lysosome-related organelles complex-1 (BLOC-1) proteins in these individuals. Here, we describe the identification of a novel nonsense mutation in BLOC1S3 (HPS-8) in a 6-yr-old Iranian boy. This mutation caused nonsense-mediated decay of BLOC1S3 mRNA and destabilized the BLOC-1 complex. Our patient's melanocytes showed aberrant localization of TYRP1, with increased plasma membrane trafficking. These findings confirm a common cellular defect for HPS patients with defects in BLOC-1 subunits. We identified only two patients with BLOC-1 defects in our cohort, suggesting that other HPS genes remain to be identified.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. andrew.cullinane@nih.gov
Andrew R
AR
Cullinane
James A
JA
Curry
Gretchen
G
Golas
James
J
Pan
Carmelo
C
Carmona-Rivera
Richard A
RA
Hess
James G
JG
White
Marjan
M
Huizing
William A
WA
Gahl
D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D005820:Genetic Testing; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010088:Oxidoreductases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
C104378:BLOC1S1 protein, human; C509457:BLOC1S3 protein, human; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D010088:Oxidoreductases; C489799:TYRP1 protein, human