title: Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability.
abstract: Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH4) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH4metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH4-activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH4and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer 52621, Israel. Electronic address: yair.anikster@sheba.health.gov.il.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, Munich 81675, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892-1851, USA; Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, VA 22042, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Pode-Shakked
authors.affiliation: Division of Metabolism, Clinical Chemistry and Biochemistry, Division of Metabolism, Department of Pediatrics, University of Zürich, Zürich 8032, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Thöny
authors.affiliation: Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg 69120, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Guarani
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf 40225, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meissner
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf 40225, Germany.
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.affiliation: Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg 69120, Germany.
authors.forename: Friedrich K
authors.initials: FK
authors.lastname: Trefz
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Marek-Yagel
authors.affiliation: Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen 5009, Norway.
authors.forename: Aurora
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Huttlin
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joao A
authors.initials: JA
authors.lastname: Paulo
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, Munich 81675, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Berutti
authors.affiliation: Department of Biochemistry, Robert-Debré University Hospital, APHP, Paris 75019, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.affiliation: Department of Biochemistry, Robert-Debré University Hospital, APHP, Paris 75019, France.
authors.forename: Apolline
authors.initials: A
authors.lastname: Imbard
authors.affiliation: UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris 75019, France.
authors.forename: Imen
authors.initials: I
authors.lastname: Dorboz
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer 52621, Israel; Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Gali
authors.initials: G
authors.lastname: Heimer
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Landau
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Ziv-Strasser
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892-1851, USA; Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, VA 22042, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
authors.forename: May Christine V
authors.initials: MCV
authors.lastname: Malicdan
authors.affiliation: Division of Metabolism, Clinical Chemistry and Biochemistry, Division of Metabolism, Department of Pediatrics, University of Zürich, Zürich 8032, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Gemperle-Britschgi
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn 53127, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn 53127, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.affiliation: Division of Metabolism, Clinical Chemistry and Biochemistry, Division of Metabolism, Department of Pediatrics, University of Zürich, Zürich 8032, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Meili
authors.affiliation: Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Berne 3012, Switzerland; Department of Clinical Research, University of Bern, Berne 3012, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Keller
authors.affiliation: Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Berne 3012, Switzerland.
authors.forename: Rémy
authors.initials: R
authors.lastname: Bruggmann
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, Munich 81675, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, Munich 81675, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, NIH, Bethesda, MD 20892-9400, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Gerard
authors.initials: G
authors.lastname: Schwartz
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg 69120, Germany.
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
authors.affiliation: Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg 69120, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr. 32, Munich 81675, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg 69120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Opladen
authors.affiliation: UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris 75019, France; Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris 75019, France. Electronic address: manuel.schiff@aphp.fr.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D016022:Case-Control Studies; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism; D004421:Dystonia / Q000235:genetics*; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010649:Phenylalanine / Q000378:metabolism; D010651:Phenylalanine Hydroxylase / Q000235:genetics; D010661:Phenylketonurias / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012701:Serotonin / Q000172:deficiency / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: C484558:DNAJC12 protein, human; D018840:HSP70 Heat-Shock Proteins; D012097:Repressor Proteins; D001708:Biopterins; D012701:Serotonin; D014443:Tyrosine; D010649:Phenylalanine; D014364:Tryptophan; D010651:Phenylalanine Hydroxylase; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; C003402:sapropterin; D004298:Dopamine
keywords: BH(4); DNAJC12; dystonia; hyperphenylalaninemia; neurotransmitter deficiency; newborn screening; phenylketonuria; tetrahydrobiopterin