Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.
We studied two related families (HHH013 and HHH015) with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, a disorder of the urea cycle and ornithine degradation pathway, who have the same novel ornithine transporter (ORNT1) genotype (T32R) but a variable phenotype. Both HHH015 patients are doing well in school and are clinically stable; conversely, the three affected HHH013 siblings had academic difficulties and one suffered recurrent episodes of hyperammonemia and ultimately died. Overexpression studies revealed that the product of the ORNT1-T32R allele has residual function. Ornithine transport studies in HHH015 fibroblasts, however, showed basal activity similar to fibroblasts carrying nonfunctional ORNT1 alleles. We also examined two potential modifying factors, the ORNT2 gene and the mitochondrial DNA lineage (haplogroup). Haplogroups, associated with specific diseases, are hypothesized to influence mitochondrial function. Results demonstrated that both HHH015 patients are heterozygous for an ORNT2 gain of function polymorphism and belong to haplogroup A whereas the HHH013 siblings carry the wild-type ORNT2 and are haplogroup H. These observations suggest that the ORNT1 genotype cannot predict the phenotype of HHH patients. The reason for the phenotypic variability is unknown, but factors such as redundant transporters and mitochondrial lineage may contribute to the neuropathophysiology of HHH patients.
Camacho
José A
JA
Department of Pediatrics, Division of Human Genetics, University of California, Irvine, CA 92697-3940, USA. jcamacho@uci.edu
Mardach
Rebecca
R
Rioseco-Camacho
Natalia
N
Ruiz-Pesini
Eduardo
E
Derbeneva
Olga
O
Andrade
Dario
D
Zaldivar
Frank
F
Qu
Yong
Y
Cederbaum
Stephen D
SD
D000293:Adolescent; D000328:Adult; D026923:Amino Acid Transport Systems, Basic; D002648:Child; D020159:Citrullinemia / Q000175:diagnosis* / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D022124:Hyperammonemia / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008659:Metabolic Diseases / Q000175:diagnosis* / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins; D009154:Mutation; D009952:Ornithine / Q000097:blood* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D011506:Proteins / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D013577:Syndrome
D026923:Amino Acid Transport Systems, Basic; D004272:DNA, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins; D011506:Proteins; D012333:RNA, Messenger; C442901:SLC25A15 protein, human; D009952:Ornithine