Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2.
We report on the molecular etiology of an unusual clinical phenotype associating congenital neutropenia, thrombocytopenia, developmental delay, and hypopigmentation. Using genetic linkage analysis and targeted gene sequencing, we defined a homozygous genomic deletion in AP3B1, the gene encoding the beta chain of the adaptor protein-3 (AP-3) complex. The mutation leads to in-frame skipping of exon 15 and thus perturbs proper assembly of the heterotetrameric AP-3 complex. Consequently, trafficking of transmembrane lysosomal proteins is aberrant, as shown for CD63. In basal keratinocytes, the incorporated immature melanosomes were rapidly degraded in large phagolysosomes. Despite distinct ultramorphologic changes suggestive of aberrant vesicular maturation, no functional aberrations were detected in neutrophil granulocytes. However, a comprehensive immunologic assessment revealed that natural killer (NK) and NKT-cell numbers were reduced in AP-3-deficient patients. Our findings extend the clinical and molecular phenotype of human AP-3 deficiency (also known as Hermansky-Pudlak syndrome, type 2) and provide further insights into the role of the AP-3 complex for the innate immune system.
Jung
Johannes
J
Division of Rheumatology and Clinical Immunology, Medical Center, Freiburg University Hospital, Germany.
Bohn
Georg
G
Allroth
Anna
A
Boztug
Kaan
K
Brandes
Gudrun
G
Sandrock
Inga
I
Schäffer
Alejandro A
AA
Rathinam
Chozhavendan
C
Köllner
Inga
I
Beger
Carmela
C
Schilke
Reinhard
R
Welte
Karl
K
Grimbacher
Bodo
B
Klein
Christoph
C
D033963:Adaptor Protein Complex 3 / Q000235:genetics*; D033966:Adaptor Protein Complex beta Subunits / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis / Q000379:methods; D017353:Gene Deletion; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D009504:Neutrophils / Q000276:immunology; D010375:Pedigree; D010641:Phenotype
C439973:AP3B1 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits