Molecular characteristics
WDR81 (WD Repeat-Containing Protein 81) gene is located at 17p13.3 and encodes a multi-domain transmembrane protein that acts as a negative regulator of PI3 kinase/PI3K activity and is thought to play a role in endolysosomal trafficking. WDR81 is predominantly expressed in the brain.
Mutations and pathophysiology
Mutations in WDR81 cause Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 2 or Congenital Hydrocephalus 3 associated with brain anomalies. The latter more severe phenotype is usually associated with severe loss of function mutations.
The following are a few selected examples of pathogenic variants in WDR81:
- Gulsuner et al. (2011) reported homozygosity for c. 2567C>T mutation in WDR81 (NM_001163809.1) leading to a p.Pro856Leu substitution. The patients were born to a consanguineous Turkish family and displayed features consistent with Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome-2 (CAMRQ2).
- In another similarly affected patient born to a consanguineous Yemeni family, Komara et al. (2016) identified a homozygous c.3997C>T mutation leading to a p.Arg1333*.
- Alazami et al. (2015) reported a mutation in WDR81 (NM_001163809:c.845G>A, p.Gly282Glu), leading to Congenital Hydrocephalus 3. The affected patient died neonatally due to hydranencephaly and severe cerebellar hypoplasia. This case was independently confirmed by Shaheen et al. (2017).
- Congenital Hydrocephalus 3 was reported in two consanguineous Saudi families. Shaheen et al. (2017) identified a homozygous truncating mutation in WDR81 (NM_001163809.1: c.3286C>T, p. Gln1096*) leading to stillbirth with severe hydrocephalus and cerebellar hypoplasia. The other family presented with similar findings in the stillbirth, and a homozygous missense mutation was identified (NM_001163809.1:c.845G>A, p. [Gly282Glu]). These mutations were reported to cause severe loss of function in the gene, which may explain the more severe phenotype displayed Congenital Hydrocephalus 3.