Neurodegeneration with brain iron accumulation (NBIA) subtypes pathway (WP4577)

Homo sapiens

Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term for 12 disease subtypes, all characterized by the build-up of iron within the brain. One of these subtypes is beta-propeller protein-associated neurodegeneration (BPAN) caused by a mutation in the WDR45 gene. This protein is involved in the autophagy pathway; the exact mechanism is still unknown. Other NBIA subtypes are PKAN, CoPAN, and FAHN. PKAN and CoPAN are involved in Coenzyme A synthesis within mitochondria and FAHN is found in myelin synthesis. Dysfunctioning of these pathways leads to a phenotype characterized by developmental delay and intellectual disabilities. Nevertheless, the exact relation between mutation and phenotype remains unknown.


G. Keulen , Denise Slenter , Egon Willighagen , Friederike Ehrhart , Kristina Hanspers , Marvin Martens , Martina Summer-Kutmon , and Eric Weitz


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Homo sapiens


Rare Diseases


Pathway Ontology

disease pathway

Cell Type Ontology


Disease Ontology

neurodegeneration with brain iron accumulation


Label Type Compact URI Comment
Palmitoyl-CoA Metabolite chebi:57379
(R)-4'-phosphopantothenate Metabolite chebi:10986
L-cysteine Metabolite chebi:35235
Sphingomyelin Metabolite chebi:17636
3-Dehydrosphinganine Metabolite chebi:17862
Dihydrosphingosine Metabolite pubchem.compound:46878428
D-pantetheine 4'-phosphate Metabolite chebi:61723
(R)-pantothenate Metabolite chebi:29032
Diphosphate Metabolite chebi:33019
Ceramide Metabolite chebi:17761
Coenzyme A Metabolite chebi:57287
1,2-saturated fatty acid Metabolite chebi:83955
(2R)-2-hydroxy fatty acid anion Metabolite chebi:76177
L-serine Metabolite chebi:33384
Dihydroceramide Metabolite chebi:139048
Acetyl-CoA Metabolite chebi:57288
Fe(II)-cytochrome b5 Metabolite chebi:29033
Malonyl-CoA Metabolite chebi:57384
3'-dephospho-CoA Metabolite chebi:57328
Sphingolipids Metabolite chebi:26739
N-[(R)-4'-Phosphopantothenoyl]-L-cysteine Metabolite chebi:59458
Fe(III)-cytochrome b5 Metabolite chebi:29034
PtdIns3P Metabolite chebi:26034
SPTLC1 GeneProduct ensembl:ENSG00000090054
ACACA GeneProduct ensembl:ENSG00000278540
FA2H GeneProduct ensembl:ENSG00000103089
MECP2 GeneProduct ensembl:ENSG00000169057
COASY GeneProduct ensembl:ENSG00000068120
PIK3C3 GeneProduct ensembl:ENSG00000078142
ATG10 GeneProduct ensembl:ENSG00000152348
WIPI2 GeneProduct ensembl:ENSG00000157954
ATG7 GeneProduct ensembl:ENSG00000197548
ATG14 GeneProduct ensembl:ENSG00000126775
AKT1S1 GeneProduct ensembl:ENSG00000204673
ATG13 GeneProduct ensembl:ENSG00000175224
RB1CC1 GeneProduct ensembl:ENSG00000023287
AMPK GeneProduct ensembl:ENSG00000132356
RHEB GeneProduct ensembl:ENSG00000106615
ULK1 GeneProduct ensembl:ENSG00000177169
ATG16L1 GeneProduct ensembl:ENSG00000085978
ATG12 GeneProduct ensembl:ENSG00000145782
BECN1 GeneProduct ensembl:ENSG00000126581
DEPTOR GeneProduct ensembl:ENSG00000155792
LC3 GeneProduct ensembl:ENSG00000101460
ATG2A GeneProduct ensembl:ENSG00000110046
LKB1 GeneProduct ensembl:ENSG00000118046
ATG7 GeneProduct ensembl:ENSG00000197548
PIK3R4 GeneProduct ensembl:ENSG00000196455
TSC1 GeneProduct ensembl:ENSG00000165699
ATG5 GeneProduct ensembl:ENSG00000057663
MLST8 GeneProduct ensembl:ENSG00000167965
TSC2 GeneProduct ensembl:ENSG00000103197
ATG12 GeneProduct ensembl:ENSG00000145782
WIPI1 GeneProduct ensembl:ENSG00000070540
ATG4 GeneProduct ensembl:ENSG00000101844
WDR45 GeneProduct ensembl:ENSG00000196998
MTOR GeneProduct ensembl:ENSG00000198793
RPTOR GeneProduct ensembl:ENSG00000141564
ATG101 GeneProduct ensembl:ENSG00000123395
ATG3 GeneProduct ensembl:ENSG00000144848
ATG12 GeneProduct ensembl:ENSG00000145782
ATG12 GeneProduct ensembl:ENSG00000145782
ATG5 GeneProduct ensembl:ENSG00000057663
LC3 GeneProduct ensembl:ENSG00000101460
LC3 GeneProduct ensembl:ENSG00000101460
LC3 GeneProduct ensembl:ENSG00000101460
COASY GeneProduct ensembl:ENSG00000068120
PLA2G6 GeneProduct ensembl:ENSG00000184381
DCAF17 GeneProduct ensembl:ENSG00000115827
WDR45 GeneProduct ensembl:ENSG00000196998
PLA2G6 GeneProduct ensembl:ENSG00000184381
C19orf12 GeneProduct ensembl:ENSG00000131943
FA2H GeneProduct ensembl:ENSG00000103089
ATP13A2 GeneProduct ensembl:ENSG00000159363
GTPBP2 GeneProduct ensembl:ENSG00000172432
COASY GeneProduct ensembl:ENSG00000068120
PANK2 GeneProduct ensembl:ENSG00000125779
FTL GeneProduct ensembl:ENSG00000087086
SCPx GeneProduct ensembl:ENSG00000116171
CP GeneProduct ensembl:ENSG00000047457
PANK2 Protein ensembl:ENSG00000125779


  1. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Huang J, Manning BD. Biochem J. 2008 Jun 1;412(2):179–90. PubMed Europe PMC Scholia
  2. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Memmott RM, Dennis PA. Cell Signal. 2009 May;21(5):656–64. PubMed Europe PMC Scholia
  3. mTOR regulation of autophagy. Jung CH, Ro SH, Cao J, Otto NM, Kim DH. FEBS Lett. 2010 Apr 2;584(7):1287–95. PubMed Europe PMC Scholia
  4. The Beclin 1-VPS34 complex--at the crossroads of autophagy and beyond. Funderburk SF, Wang QJ, Yue Z. Trends Cell Biol. 2010 Jun;20(6):355–62. PubMed Europe PMC Scholia
  5. Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Polson HEJ, de Lartigue J, Rigden DJ, Reedijk M, Urbé S, Clague MJ, et al. Autophagy. 2010 May;6(4):506–22. PubMed Europe PMC Scholia
  6. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Mol Cell. 2010 Jun 11;38(5):768–74. PubMed Europe PMC Scholia
  7. AMPK -> ULK1 -> autophagy. Roach PJ. Mol Cell Biol. 2011 Aug;31(15):3082–4. PubMed Europe PMC Scholia
  8. Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. Leoni V, Strittmatter L, Zorzi G, Zibordi F, Dusi S, Garavaglia B, et al. Mol Genet Metab. 2012 Mar;105(3):463–71. PubMed Europe PMC Scholia
  9. Architecture of human mTOR complex 1. Aylett CHS, Sauer E, Imseng S, Boehringer D, Hall MN, Ban N, et al. Science. 2016 Jan 1;351(6268):48–52. PubMed Europe PMC Scholia
  10. Regulation and function of AMPK in physiology and diseases. Jeon SM. Exp Mol Med. 2016 Jul 15;48(7):e245. PubMed Europe PMC Scholia
  11. Deptor: not only a mTOR inhibitor. Catena V, Fanciulli M. J Exp Clin Cancer Res. 2017 Jan 13;36(1):12. PubMed Europe PMC Scholia
  12. WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Bakula D, Müller AJ, Zuleger T, Takacs Z, Franz-Wachtel M, Thost AK, et al. Nat Commun. 2017 May 31;8:15637. PubMed Europe PMC Scholia
  13. The mammalian ULK1 complex and autophagy initiation. Zachari M, Ganley IG. Essays Biochem. 2017 Dec 12;61(6):585–96. PubMed Europe PMC Scholia
  14. Classification and molecular pathogenesis of NBIA syndromes. Di Meo I, Tiranti V. Eur J Paediatr Neurol. 2018 Mar;22(2):272–84. PubMed Europe PMC Scholia
  15. MECP2 Mutation Interrupts Nucleolin-mTOR-P70S6K Signaling in Rett Syndrome Patients. Olson CO, Pejhan S, Kroft D, Sheikholeslami K, Fuss D, Buist M, et al. Front Genet. 2018 Dec 19;9:635. PubMed Europe PMC Scholia