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Am J Hum Genet. 2017 Feb 2;100(2):257-266. doi: 10.1016/j.ajhg.2017.01.002. Epub 2017 Jan 26.

Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability.

Author information

1
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.
2
Institute of Human Genetics, Technische Universität München, Trogerstr. 32, Munich 81675, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany.
3
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.
4
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.
5
Division of Metabolism, Clinical Chemistry and Biochemistry, Division of Metabolism, Department of Pediatrics, University of Zürich, Zürich 8032, Switzerland.
6
Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, Heidelberg 69120, Germany.
7
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
8
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf 40225, Germany.
9
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.
10
Department of Biomedicine and K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen 5009, Norway.
11
Department of Biochemistry, Robert-Debré University Hospital, APHP, Paris 75019, France.
12
UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris 75019, France.
13
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.
14
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.
15
Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer 52621, Israel.
16
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.
17
Institute of Human Genetics, University of Bonn, Bonn 53127, Germany.
18
Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Berne 3012, Switzerland; Department of Clinical Research, University of Bern, Berne 3012, Switzerland.
19
Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Berne 3012, Switzerland.
20
NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, NIH, Bethesda, MD 20892-9400, USA.
21
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.
22
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
23
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.

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 BH4 metabolism 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 BH4 and/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.

KEYWORDS:

BH(4); DNAJC12; dystonia; hyperphenylalaninemia; neurotransmitter deficiency; newborn screening; phenylketonuria; tetrahydrobiopterin

PMID:
28132689
PMCID:
PMC5294665
DOI:
10.1016/j.ajhg.2017.01.002
[Indexed for MEDLINE]
Free PMC Article

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