Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-1851, USA. mhuizing@mail.nih.gov
M
M
Huizing
B
B
Pederson
R A
RA
Hess
A
A
Griffin
A
A
Helip-Wooley
W
W
Westbroek
H
H
Dorward
K J
KJ
O'Brien
G
G
Golas
E
E
Tsilou
J G
JG
White
W A
WA
Gahl
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020460:Melanosomes / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
C493901:HPS6 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D004247:DNA