PCDH12

The PCDH12 (Protocadherin-12) gene is part of the protocadherin gene family, a subgroup within the larger cadherin superfamily. It encodes a calcium-dependent cell adhesion protein characterized by an extracellular domain with six cadherin repeats, a transmembrane domain, and a unique cytoplasmic tail that distinguishes it from classical cadherins. PCDH12 is located on chromosome 5q31. Given their critical role in the development and maintenance of neuronal circuits, any genetic alterations in protocadherins, including PCDH12, have been implicated in the emergence of neurodevelopmental and neuropsychiatric disorders.

Biological Function

PCDH12 is widely expressed, particularly in the central nervous system and endothelial cells. The specific functions of PCDH12 in the nervous system are not yet fully understood.
PCDH12 is expressed in angiogenic endothelial cells, mesangial cells of kidney glomeruli, and glycogen cells of the mouse placenta.
The extracellular domain of PCDH12 has been detected in human serum and urine, indicating that it undergoes shedding in vivo.
Importantly, studies have shown an increase in circulating levels of PCDH12 in pregnant women who later develop pre-eclampsia, a common pregnancy complication that poses significant risks to both maternal and fetal health.
PCDH12 may play a crucial role in human placental development and its activity could be modulated by proteolytic cleavage in response to external factors, such as cytokines or pathological conditions.
PCDH12 is essential for the proper development of cerebral organoids, where it plays a critical role in the differentiation of progenitor cells and the establishment of neuronal layers.
PCDH12 facilitates neuronal migration through a mechanism that involves ectodomain shedding mediated by metalloproteinases.

Mutations

Bi-allelic homozygous and missense compound heterozygous truncating variants in the PCDH12 gene have been documented in the literature.

Incidence

As of now, only 25 families have been reported with PCDH12-associated diseases. Biallelic variants in the PCDH12 gene have been identified in a total of 39 individuals documented across ten publications, spanning diverse ethnic backgrounds.

Associated Conditions

Bi-allelic truncating PCDH12 variants have been linked to a range of clinical conditions, including diencephalic-mesencephalic junction dysplasia syndrome.

Symptoms

Individuals with PCDH12 deficiency often present with a spectrum of neurological and developmental issues, such as developmental delay, movement disorders, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications.

Research at Northwestern

Ongoing research projects at the Center for Autism and Neurodevelopment, particularly in the Guemez-Gamboa lab, is focused on understanding how pathogenic variants in the PCDH12 gene contribute to neurodevelopmental disorders. A key aspect of this research involves creating human-derived stem cell models to explore the impact of loss-of-function variants in PCDH12 on brain development. These models are essential for testing and advancing potential new therapies, ultimately aiming to improve outcomes for individuals affected by these disorders.

Key publications include:

Rakotomamonjy J, Rylaarsdam L, Fares-Taie L, McDermott S, Davies D, Yang G, et al.
PCDH12 loss results in premature neuronal differentiation and impeded migration in a cortical organoid model.
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Important publications from other laboratories

PCDH12 variants are associated with basal ganglia anomalies and exudative vitreoretinopathy
Accogli A, El Kosseifi C, Saint-Martin C, et al.
Eur J Med Genet. 2022 Feb;65(2):104405.
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The phenotypic spectrum of PCDH12-associated disorders – Five new cases and review of the literature
Fazeli W, Bamborschke D, Moawia A, et al.
Eur J Paediatr Neurol. 2022 Jan;36:7-13.
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Ophthalmic phenotypes associated with biallelic loss-of-function PCDH12 variants
Mattioli F, Voisin N, Preikšaitienė E, et al.
Am J Med Genet A. 2021 Apr;185(4):1275-1281.
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Homozygous PCDH12 variants result in phenotype of cerebellar ataxia, dystonia, retinopathy, and dysmorphism
Vineeth VS, Das Bhowmik A, Balakrishnan S, et al.
J Hum Genet. 2019 Feb;64(2):183-189.
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Loss of Protocadherin-12 leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome
Guemez-Gamboa A, Çağlayan AO, Stanley V, et al.
Ann Neurol. 2018 Nov;84(5):638-647.
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A case of new PCDH12 gene variants presented as dyskinetic cerebral palsy with epilepsy
Suzuki-Muromoto S, Wakusawa K, Miyabayashi T, et al.
J Hum Genet. 2018 Jun;63(6):749-753.
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Loss of function of PCDH12 underlies recessive microcephaly mimicking intrauterine infection
Aran A, Rosenfeld N, Jaron R, et al.
Neurology. 2016 May 24;86(21):2016-2024.
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Protocadherin-12 cleavage is a regulated process mediated by ADAM10 protein: evidence of shedding up-regulation in pre-eclampsia
Bouillot S, Tillet E, Carmona G, et al.
J Biol Chem. 2011 Apr 29;286(17):15195-204.
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Genetic Testing

Currently, pathogenic variants in the PCDH12 gene are identified through whole genome or whole exome sequencing.

Clinical Trials

Currently, there are no clinical trials specifically targeting PCDH12-associated mutations.