TABLE 2.
Summary of genetic mechanism in the pathogenesis of hydrocephalus.
| Disorder/etiopathogenesis | Species/strain | Genetic locus | Genetic trait/chromosome | Reference(s) |
|---|---|---|---|---|
| Hypersecretory: over production of CSF by choroid plexus | Human/mouse | E2f5; Tg737orpk | Autosomal recessive | Wagner et al. (2003); Banizs et al. (2005); Lindeman et al. (1998); Putoux et al. (2011) |
| Congenital/obstructive: defective ependymal cilia/flow/neural tube, and resultant closure of aqueduct | Human/mouse | Mdnah5, KIF7, VANGL1, 2, SMARCC1, TRIM71, PTCH1 | Wagner et al. (2003); Banizs et al. (2005); Lindeman et al. (1998); Putoux et al. (2011); Fruey et al. (2018); Jin et al. (2020); Kibar et al. (2011); Mastromoro et al. (2021); Kundishora et al. (2021) | |
| iNPH: dysfunction of the glymphatic pathway and sub-ischemia | Human/mouse | AQP4, Dp71 | Eide and Hansson (2018) | |
| Congenital/obstructive/communicating/iNPH: dysfunction of the glymphatic pathway due to aberrant motile cilium on ependymal cells | Human/mouse | Ccdc39, Celsr2, Celsr3, Cetn2, Dvls, FoxJ1, Hydin, Mdnah5, Pkd1, Tg737, Daple, Dnah14, Cfap43, Cwh43, FMN2, EML1, TMEM67, ZCCHC8 | Kundishora et al. (2021); Yamada et al. (2021); Abdi et al. (2018); Wallmeier et al. (2019); Sotak and Gleeson (2012); Lechtreck et al. (2008); Takagishi et al. (2017); Morimoto et al. (2019); Yang et al. (2021); Law et al. (2014); Shaheen et al. (2017); McKnight et al. (2021) | |
| Defective cilia orientation/aberrant CSF flow | Human | CCDC88C | Autosomal recessive | Marguet et al. (2021); Ohata et al. (2014) |
| Congenital: defective neural cell adhesion/stenosis of the aqueduct of Sylvius/agenesis of corpus callosum | Human | L1CAM | X-linked/Xq28 | Adle-Biassette et al. (2013); Jouet et al. (1993); Okamoto et al. (2004); Willems et al. (1987); Bousquet et al. (2021); Wang et al. (2021); Etchegaray et al. (2020) |
| Aberrant vesicle trafficking | Human | AP1S2 | X-linked | Kousi and Katsanis (2016); Marguet et al. (2021); Yang et al. (2019) |
| Disruption of the planar cell polarity pathway | Human | MPDZ | Autosomal recessive | Al-Jezawi et al. (2018); Sotak and Gleeson (2012) |
| Aqueductal stenosis without intellectual disability | Human | Unknown | Autosomal dominant/8q12.2-q21.2 | Verhagen et al. (1998); Vincent et al. (1994) |
| SCO abnormalities/cerebral aqueduct closure/corpus callosum absence/free radical damage/abnormal cerebral hemisphere formation | Rat/HTX | Cck, Nfix, Xdh, Gsta1, Pax-6, Fkhr | Chr9, Chr10, Chr11, Chr17 | Zhang et al. (2006); Miller et al. (2006); Oi et al. (1996); Somera and Jones (2004); Somera and Jones (2002) |
| Perturbation of growth factor signaling for cell function | Rat/HTX | TGFB, FGF-2, IGFBP-1, SOCS | Zhang et al. (2006); Li et al. (2005); Doublier et al. (2000); Ohmiya et al. (2001); Krebs et al. (2004) | |
| Extracellular matrix disruption | Rat/HTX | TGFB1, TIMP-1 | Zechel et al. (2002) | |
| Aqueduct stenosis | Rat | LEW/Jms | Miller et al. (2006) | |
| Symptomatic hydrocephalus of Dandy-Walker syndrome | Rat | 6-AN | Oi et al. (1996) | |
| Defective ependymal cell migration and proliferation/enhanced Notch signaling activity/aqueduct stenosis | Mouse | Rnd3 | Lin et al. (2013) | |
| Defective embryo development and ventricular size | Mouse | Vent8a, Vent4b, Vent7c | Chr4, Chr7, Chr8 | Zhang et al. (2006); Zygourakis and Rosen (2003) |
| Defective cytoskeleton/ependymal cell malfunction | Human/Hy3 mouse | Bdnf, Mdnah5 | Chr8 | Zhang et al. (2006); Davy and Robinson (2003); Jimenez et al. (2001); Wagner et al. (2003); Ibanez-Tallon et al. (2004) |
| Defective mesenchymal cell/defective PC and SCO/collapse of the cerebral aqueduct | Mouse | Msx1, CYP2J2, RFX4_v3 | Zhang et al. (2006); Blackshear et al. (2003) | |
| Defective differentiation of arachnoid cells | Human/mouse | Mf1, FREAC3 | Zhang et al. (2006); Kume et al. (1998) | |
| Defective cellular membrane fusion/abnormal development of the neuronal cells | Hyh mouse | a-SNAP, aPKC, VAMP-7 | Hong et al. (2004); Chae et al. (2004) | |
| Intracranial hemorrhage and subcortical heterotopia | Mouse | Hhy | Chr12 | Kuwamura et al. (2004) |
| Defective brain development and edematous periventricular white matter | Mouse | Otx2 | Makiyama et al. (1997) |
Abbreviations: 6-AN, 6-aminonicotinamide; AP1S2, adapter-related protein complex 1, sigma-2 subunit; aPKC, atypical protein kinase C; a-SNAP, soluble NSF attachment protein a; CCDC88C, coiled-coil domain-containing protein 88c; Cck, cholecystokinin; CSF, cerebrospinal fluid; Ch, congenital hydrocephalus; Chr, chromosome; E2f5, E2F transcription factor 5; FGF-2, fibroblast growth factor-2; Fkhr, fork-head transcription factor BF-1; Hhp, hemorrhagic hydrocephalus; Hyh, hydrocephalus and hop gait; Hy3, hydrocephalus-3; IGFBP-1, IGF binding protein-1; iNPH, idiopathic normal pressure hydrocephalus; L1CAM, L1 cell adhesion molecule; MPDZ, multiple PDZ domain protein; Mdnah5, axonemal heavy chain 5 gene; Mf1, Foxc1; Nfix, nuclear factor 1; PC, posterior commissure; Rnd3, Rho family guanosine triphosphatase 3; RFX4_v3, regulatory factor X4; SCO, subcommissural organ; SOCS, cytokine signaling protein; TGFB, transforming growth factor-beta; VAMP-7, vesicle-associated membrane protein-7; Wnt, wingless/integrated; Xdh, xanthine dehydrogenase.