Brain calcifications and PCDH12 variants

Abstract

Objective:To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications.Methods:We performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC).Results:We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency <0.001) PCDH12 predicted damaging missense heterozygous variants in 3 unrelated patients, albeit with no segregation data available.Conclusions:Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. A putative role for PCDH12 variants remains to be determined in PFBC.

SMAD6 transduces endothelial cell flow responses required for blood vessel homeostasis

“…4d, compare Flow-NT to Flow-Smad6 KD). Of these, the protocadherin PCDH12 was chosen for further analysis, since PCDH12 is selectively expressed in arterial endothelial cells, and its deletion leads to changes in murine arterial blood pressure, while human mutations are associated with brain arterial calcification [52][53][54]. Validation of PCDH12 expression changes via qRT-PCR showed significant upregulation of PCDH12 expression with homeostatic laminar flow, and this increase was blunted to 60% of static control levels in flowed endothelial cells with reduced Smad6 levels (Fig.…”

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

“…18 PCDH12 variants have been associated with schizophrenia, 19 and recently biallelic pathogenic variants have been linked to microcephaly, seizures, spasticity with brain calcifications [OMIM#251280]. 20,21 Our report extends the phenotypic spectrum associated with PCHD12 mutations and adds to the growing body of neurological disorders linked with altered protocadherins.…”

Random forest-integrated analysis in AD and LATE brain transcriptome-wide data to identify disease-specific gene expression

“…The 23rd and 24th ranked genes, ARMCX6 and BRD4 , were linked to impairments in cognition and memory [ 44 – 46 ], which are regarded as the common symptoms of dementia. The 26th ranked gene PCDH12 was previously associated with brain calcifications [ 47 ], which could cause memory loss, personality changes, and diminished intellectual function [ 53 ], thereby potentially leading to psychosis or neurocognitive disorder [ 54 , 55 ]. The 31st ranked gene HSFY1 was found to affect APOE4 genotypes, while the patients with different APOE4 genotypes, such as APOE4-negative and APOE4-positive, possibly have different decline speeds on language, attention, executive, and visuospatial functioning [ 56 ].…”