title: Homozygosity mapping and whole-exome sequencing to detect SLC45A2 and G6PC3 mutations in a single patient with oculocutaneous albinism and neutropenia.
abstract: We evaluated a 32-year-old woman whose oculocutaneous albinism (OCA), bleeding diathesis, neutropenia, and history of recurrent infections prompted consideration of the diagnosis of Hermansky-Pudlak syndrome type 2. This was ruled out because of the presence of platelet δ-granules and absence of AP3B1 mutations. As parental consanguinity suggested an autosomal recessive mode of inheritance, we employed homozygosity mapping, followed by whole-exome sequencing, to identify two candidate disease-causing genes, SLC45A2 and G6PC3. Conventional dideoxy sequencing confirmed pathogenic mutations in SLC45A2, associated with OCA type 4 (OCA-4), and G6PC3, associated with neutropenia. The substantial reduction of SLC45A2 protein in the patient's melanocytes caused the mislocalization of tyrosinase from melanosomes to the plasma membrane and also led to the incorporation of tyrosinase into exosomes and secretion into the culture medium, explaining the hypopigmentation in OCA-4. Our patient's G6PC3 mRNA expression level was also reduced, leading to increased apoptosis of her fibroblasts under endoplasmic reticulum stress. To our knowledge, this report describes the first North American patient with OCA-4, the first culture of human OCA-4 melanocytes, and the use of homozygosity mapping, followed by whole-exome sequencing, to identify disease-causing mutations in multiple genes in a single affected individual.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. andrew.cullinane@nih.gov
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cullinane
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Brien
authors.forename: James A
authors.initials: JA
authors.lastname: Curry
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Maynard
authors.forename: Hannah
authors.initials: H
authors.lastname: Carlson-Donohoe
authors.forename: Carla
authors.initials: C
authors.lastname: Ciccone
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D000328:Adult; D016115:Albinism, Oculocutaneous / Q000150:complications* / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D017496:Hypopigmentation / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics; D008544:Melanocytes / Q000166:cytology; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D009503:Neutropenia / Q000150:complications* / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013921:Thrombocytopenia / Q000150:complications / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D026901:Membrane Transport Proteins; C510061:SLC45A2 protein, human; D005952:Glucose-6-Phosphatase; C492193:G6PC3 protein, human