Loss of Protocadherin‐12Leads to Diencephalic‐Mesencephalic Junction Dysplasia Syndrome

Abstract

DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.

Protocadherins at the Crossroad of Signaling Pathways

“…All members of the δ1-Pcdh family and the majority of the δ2-Pcdh family, with the exception of Pcdh18, have been associated to the regulation of dendritic initiation, growth, morphology, arbor refinement, and spine formation ( Yasuda et al, 2007 ; Piper et al, 2008 ; Bruining et al, 2015 ; Wu et al, 2015 ; Schoch et al, 2017 ; Bassani et al, 2018 ; Chang et al, 2018 ). To date, roles in axon growth, branching, guidance, and fasciculation have been described for Pcdh7 and for almost all of the δ2-Pcdhs except Pcdh8 ( Aoki et al, 2003 ; Uemura et al, 2007 ; Nakao et al, 2008 ; Piper et al, 2008 ; Leung et al, 2013 , 2015 ; Biswas et al, 2014 ; Hayashi et al, 2014 ; Cooper et al, 2015 ; Asakawa and Kawakami, 2018 ; Guemez-Gamboa et al, 2018 ). While specific synaptic roles have not yet been directly demonstrated for δ1-Pcdhs, they have been suggested to participate in synaptic maintenance and plasticity based on their expression at synapses and interaction with PP1α ( Yoshida et al, 1999 ; Vanhalst et al, 2005 ; Kim et al, 2007 ; Bruining et al, 2015 ).…”

Ophthalmic phenotypes associated with biallelic loss‐of‐function PCDH12 variants

“…While many protocadherins are specifically expressed in the central nervous system (Kim et al, 2011), PCDH12 was initially identified in mouse endothelial cells (Telo' et al, 1998). In humans, PCDH12 is well expressed in placenta, lung, and spleen and at lower level in brain (GTEx, Hum-anProteinAtlas, biogps.org data) (Bouillot et al, 2011;Guemez-Gamboa et al, 2018). Functional analysis on induced pluripotent stem cells obtained from controls' and patients' fibroblasts showed the Mutations in PCDH12 have been implicated in an autosomal recessive disorder.…”

“…exon of PCDH12 have been implicated in a neurodevelopmental disorder (OMIM: 251280) (Figure 1a) (Aran et al, 2016;Guemez-Gamboa et al, 2018;Suzuki-Muromoto et al, 2018;Vineeth et al, 2019). Consistent with nonsense-mediated decay, two of these mutations were associated with low expression of the mutated transcript (Aran et al, 2016;Vineeth et al, 2019).…”

“…The first reported individuals with homozygous PCDH12 loss-offunction variants showed a distinctive brain malformation at the diencephalic-mesencephalic junction, microcephaly, intellectual disability, and psychomotor delay (Aran et al, 2016;Guemez-Gamboa et al, 2018). Some patients presented brain calcifications, a clinical feature also observed in individuals carrying a rare heterozygous missense variant in this gene (Nicolas et al, 2017).…”

Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2

“…Recently, biallelic loss of function variants in the protocadherin 12 gene ( PCDH12 ), encoding a cell surface protein promoting cell adhesion and neurite outgrowth, have been identified in 14 patients with DMJ dysplasia from eight independent families. Patients presented a peculiar clinical-radiological phenotype characterized by progressive microcephaly, severe cognitive impairment, dysmorphic facies, variable spasticity and epilepsy, DMJ dysplasia with midbrain ventral cleft, callosal hypoplasia, and in most cases also calcifications (Guemez-Gamboa et al , 2018). Of note, PCDH12 mutations were found in two of the three families originally described (Zaki et al , 2012), while no pathogenic variants were identified in the third family with a different phenotype of massively dilated lateral ventricles, further supporting the hypothesis of different genetic mechanisms underlying DMJ disorders.…”