Monocarboxylate transporter 1 deficiency and ketone utilization.
Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in a patient with recurrent, severe ketoacidosis and identified a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 (SLC16A1, also called MCT1). Genetic analysis in 96 patients suspected of having ketolytic defects yielded seven additional inactivating mutations in MCT1, both homozygous and heterozygous. Mutational status was found to be correlated with ketoacidosis severity, MCT1 protein levels, and transport capacity. Thus, MCT1 deficiency is a novel cause of profound ketoacidosis; the present work suggests that MCT1-mediated ketone-body transport is needed to maintain acid-base balance.
From the Division of Pediatrics, Department of Metabolic Diseases (P.M.H., G.V.), and the Division of Pediatrics, Department of Pediatric Gastroenterology (R.H.J.H.), Wilhelmina Children's Hospital, and the Center for Molecular Medicine, Department of Medical Genetics (G.R.M., M.J.G., K.D., M.H., B.Z., J.J.S., N.M.V.-D., G.H.), University Medical Center Utrecht, Utrecht, Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Academic Medical Center, Amsterdam (S.F., J.P.N.R., M.T., R.J.A.W.), the Division of Pediatrics, Department of Metabolic Diseases, and Laboratory Genetic Metabolic Diseases, Maastricht University Medical Center, Maastricht (M.E.R.-G.), and the Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen (M.C.V.) - all in the Netherlands; the National Centre for Inherited Metabolic Disorders, Children's University Hospital, Dublin, Ireland (A.A.M.); the Department of Pediatric Metabolism and Nutrition, Gazi University School of Medicine, Ankara, Turkey (I.O.); and the Department of Paediatric Metabolic Medicine, Sheffield Children's Hospital, Sheffield (M.J.S.), the Department of Metabolic Medicine, Great Ormond Street Hospital NHS Foundation Trust, London (M.C.), Chemical Pathology, Department of Laboratory Medicine, Salisbury (N.O.), and the Department of Clinical Biochemistry, Southampton General Hospital, Southampton (V.W.) - all in the United Kingdom.
Peter M
PM
van Hasselt
Sacha
S
Ferdinandusse
Glen R
GR
Monroe
Jos P N
JP
Ruiter
Marjolein
M
Turkenburg
Maartje J
MJ
Geerlings
Karen
K
Duran
Magdalena
M
Harakalova
Bert
B
van der Zwaag
Ardeshir A
AA
Monavari
Ilyas
I
Okur
Mark J
MJ
Sharrard
Maureen
M
Cleary
Nuala
N
O'Connell
Valerie
V
Walker
M Estela
ME
Rubio-Gozalbo
Maaike C
MC
de Vries
Gepke
G
Visser
Roderick H J
RH
Houwen
Jasper J
JJ
van der Smagt
Nanda M
NM
Verhoeven-Duif
Ronald J A
RJ
Wanders
Gijs
G
van Haaften
D001692:Biological Transport; D002648:Child; D002675:Child, Preschool; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D007223:Infant; D007657:Ketone Bodies / Q000378:metabolism*; D007659:Ketones / Q000378:metabolism; D007662:Ketosis / Q000235:genetics*; D027501:Monocarboxylic Acid Transporters / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D027981:Symporters / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000099233:Monocarboxylate Transport Protein 1
D007657:Ketone Bodies; D007659:Ketones; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1