Human Biochemical Genetics

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The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for abandoned populations of patients. 1. Hermansky-Pudlak syndrome (HPS) is a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of melanosomes and platelet dense bodies. There are 7 genetic subtypes of this disease. In the past year, members of the Section described a Sri Lankan patient with HPS-4, mild ocular findings in HPS-3 patients, the cellular and clinical characterization of HPS-5, abnormal intracellular trafficking in HPS-3 melanocytes in culture, and the genetic defect in a mouse model of HPS called reduced pigmentation. They continue to define the natural history of clinical involvement in the subtypes of HPS, and to perform cell biological studies of the movement of intracellular vesicles in these disorders. 2. Members of the Section admitted approximately 60 cystinosis patients to the Clinical Center, following their treatment with cysteamine and documenting the presence or absence of nonrenal complications of the disorder. A FISH-based diagnostic test for detection of the common 57-kb deletion in the cystinosis gene, CTNS, was reported. In collaboration with the National Eye Institute, members of the Section continue to investigate cysteamine eyedrops for the treatment of corneal cystine crystals. 3. The Section has expanded its expertise in alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. Several patients carrying the false diagnosis of alkaptonuria were reported by members of the Section to have minocycline-induced hyperpigmentation instead. Mutation analysis was also performed in alkaptonuria patients enrolled in the Section?s clinical studies. 4. Members of the Section reported a patient with a moderately severe disorder of free sialic acid metabolism resembling Salla disease or Infantile Free Sialic Acid Storage Disease. These disorders results from defective sialin, the lysosomal membrane transport protein that carries free sialic acid out of lysosomes. 5. Members of the Section isolated and identified the gene (SLC6A19) mutated in Hartnup disorder, a defect of renal tubule and intestinal mucosa epithelial plasma membrane transport of neutral amino acids. 6. The Section also reported hypoglycosylation of alpha-dystroglycan in patients with hereditary inclusion body myopathy due to mutations in the GNE gene, and described a patient with renal glucosuria due to mutations in SGLT2. 7. The Section continues to study Gray Platelet Syndrome (in natural history and gene-finding protocols) and Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (to define the natural history and determine outcome parameters for therapeutic intervention). A new clinical protocol to study the natural history of Hutchinson-Gilford Progeria syndrome has been approved by the NHGRI Institutional Review Board.