DNAJC12 in monoamine metabolism, neurodevelopment and neurodegeneration

Abstract

Recent studies show that mutations in DNAJC12, a co-chaperone for monoamine synthesis may cause mild hyperphenylalaninemia with infantile dystonia, young-onset parkinsonism, developmental delay and cognitive deficits. To this end, DNAJC12 gene has been included in newborn screening, most revealingly in Spain, and those results are a testament to the importance of early diagnosis and treatment in combating human diseases. However, practitioners may be unaware of these advances and it is probable that many patients, especially adults, have yet to receive molecular testing for DNAJC12. Therefore, this review summarizes genotype-phenotype relationships and treatment paradigms for patients with DNAJC12 mutations. It provides an overview of the structure of DNAJC12 protein, known mutations, domains and binding partners, and elaborates on its role in monoamine synthesis, disease etiology and pathogenesis.

Characterization ofDnajc12knock-out mice, a model of hypodopaminergia

“…1,2 Biallelic, recessively inherited pathogenic variants in DNAJC12, a member of the DNAJC family, also referred to as HSP40, induce a multitude of neurological disorders, including young-onset parkinsonism, infantile dystonia, developmental delay, intellectual disability and neuropsychiatric disorders. [3][4][5][6][7][8][9] Variants in DNAJC12 also account for a small proportion of cases of hyperphenylalaninemia (HPA), which is prominently attributed to variants in phenylalanine hydroxylase (PAH), and its cofactor tetrahydrobiopterin (BH4). 4,5,9,10 Although its function has yet to be fully understood, DNAJC12 is widely regarded as a co-chaperone for aromatic amino acid hydroxylases (AAAHs) including PAH, tyrosine hydroxylase (TH) and tryptophan hydroxylase 1 and 2 (TPH1 and TPH2).…”

“…[3][4][5][6][7][8][9] Variants in DNAJC12 also account for a small proportion of cases of hyperphenylalaninemia (HPA), which is prominently attributed to variants in phenylalanine hydroxylase (PAH), and its cofactor tetrahydrobiopterin (BH4). 4,5,9,10 Although its function has yet to be fully understood, DNAJC12 is widely regarded as a co-chaperone for aromatic amino acid hydroxylases (AAAHs) including PAH, tyrosine hydroxylase (TH) and tryptophan hydroxylase 1 and 2 (TPH1 and TPH2). 3,4 Patients with DNAJC12 variants have reduced levels of dopamine (DA) and serotonin metabolites in their cerebrospinal fluid, congruent with the role of DNAJC12 as a co-chaperone for TH and TPH2, respectively.…”

“…3,4 Patients with DNAJC12 variants have reduced levels of dopamine (DA) and serotonin metabolites in their cerebrospinal fluid, congruent with the role of DNAJC12 as a co-chaperone for TH and TPH2, respectively. [3][4][5][6]9 Besides DNAJC12, several members of the DNAJC family of co-chaperones are implicated in parkinsonism including cysteine string protein-a (DNAJC5), auxilin (DNAJC6), receptor-mediated endocytosis-8 (DNAJC13) and cyclic G associated kinase (DNAJC26). [11][12][13][14] We have similarly identified heterozygous mutations in guanosine triphosphate (GTP) cyclohydrolase I (GCH1), the rate-limiting step in the conversion of GTP to tetrahydrobiopterin (BH4), in patients with postural dystonia in childhood that becomes generalized 15,16 or with late-onset Parkinson's disease (PD).…”