De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family

Castilla‐Vallmanya, Laura; Gürsoy, Semra; Giray-Bozkaya, Özlem; Prat-Planas, Aina; Bullich, Gemma; Matalonga, Leslie; Centeno-Pla, Mónica; Rabionet, Raquel; Grinberg, Daniel; Balcells, Susana; Urreizti, Roser

doi:10.3390/ijms22041549

Cited by 4 publications

(4 citation statements)

References 31 publications

(37 reference statements)

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“…It should be noted that, in 1979, Polomeno and Milot suggested autosomal recessive transmission in two sporadic cases concerning individuals born to consanguineous parents [ 21 ]. However, today it is well known that dominant de novo mutations are not uncommon in consanguineous families [ 70 , 71 ].…”

Section: Geneticsmentioning

confidence: 99%

Congenital Microcoria: Clinical Features and Molecular Genetics

Angée

Nédelec

Erjavec

et al. 2021

Genes

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Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering both of these functions. It is characterized by absent or underdeveloped dilator muscle fibers and immaturity of the iridocorneal angle—where the aqueous humor is drained—which play a central role in IOP regulation. The dilator muscle anomaly is manifested in pinhole pupils (<2 mm) and thin transilluminable irises, causing both hemeralopia and photoaversion. Axial myopia and juvenile open-angle glaucoma are very frequent (80% and 30% of all cases, respectively). It has been suggested that the immaturity of the chamber angle contributes to glaucoma, and myopia has been ascribed to photoaversion and elevated IOP. Though possible, these mechanisms are insufficient. The disease has been tied to chromosome 13q32.1 structural variations. In addition to compromising iris development, modification of the 13q32.1 architecture could alter signaling pathways for axial ocular length and IOP regulation. Here, we summarize the clinical, histological, and molecular features of this disease, and we discuss the possible etiology of associated anomalies.

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Section: Geneticsmentioning

confidence: 99%

Congenital Microcoria: Clinical Features and Molecular Genetics

Angée

Nédelec

Erjavec

et al. 2021

Genes

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“…Moreover, a Wnt7a KO mouse shows reduced number of cortical progenitors due to increase differentiation of cells ultimately leading to microcephaly ( Miao et al, 2018 ), and similarly, during cortical development the LRP6 KO mice display a smaller and thinner cortical plate with layer VI and layers II–IV showing a marked decreased in the number of neurons ( Zhou et al, 2006 ), adding support that the Wnt/β-catenin complex receptor at the membrane has an essential role in cortical growth and lamination ( Figure 2 ). Interestingly, mutations in proteins that promote the secretion of Wnt ligands such as PORCN ( Castilla-Vallmanya et al, 2021 ) and Wntless ( Chai et al, 2021 ) have also been recently described to regulate cortical development.…”

Section: Wnt/β-catenin Signaling In Brain Development and Synaptic Function In Autism Spectrum Disordersmentioning

confidence: 99%

Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

Caracci

Ávila

Espinoza-Cavieres

et al. 2021

Front. Mol. Neurosci.

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Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/β-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/β-catenin signaling in ASD. First, we discuss that Wnt/β-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/β-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/β-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.

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“…The Wnt pathway acts through the activation of two alternative branches: the canonical and the non-canonical pathway ( 8 ). The activation of the non-canonical pathway, not dependent on β-catenin-driven transcription, relies on changes that affect the cytoskeletal organization and calcium homeostasis, and it is mainly related to cell differentiation, polarity, and migration ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Papillary thyroid carcinoma in Goltz–Gorlin syndrome

Costanza,

Papi,

Corrado

et al. 2023

Front. Endocrinol.

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Goltz–Gorlin syndrome (GGS), also known as focal dermal hypoplasia, is a rare X-linked disorder caused by pathogenic variants in the PORCN gene and characterized by several abnormalities, including skin and limb defects, papillomas in multiple organs, ocular malformations, and mild facial dysmorphism. To date, only approximately 300 cases have been described in the literature. A 16-year-old female patient, born with multiple congenital dysmorphisms consistent with GGS and confirmed by genetic exam, was referred to our outpatient clinic for the workup of a thyroid nodule. A thyroid ultrasound showed a bilateral nodular disease with a 17-mm large hypoechoic nodule in the right lobe. Cytological exam of fine needle aspiration biopsy was suspicious for malignancy. Thus, she underwent total thyroidectomy plus lymphadenectomy of the right central compartment. A histological exam disclosed a papillary thyroid carcinoma (PTC) with lymph node micrometastases. Radioiodine (131-Iodine) therapy was performed. At 3- and 6-month follow-up, the patient did not present either ultrasound or laboratory PTC recurrence. To our knowledge, we report the first case of PTC in a patient with GGS. Since thyroid cancer is rare among children and adolescents, we hypothesize that the PORCN pathogenic variant could be responsible for tumor susceptibility. We also provide an overview of the clinical findings on GGS patients already reported and discuss the possible pathogenetic mechanism that may underlie this rare condition, including the role of PORCN in tumor susceptibility.

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De Novo PORCN and ZIC2 Mutations in a Highly Consanguineous Family

Cited by 4 publications

References 31 publications

Congenital Microcoria: Clinical Features and Molecular Genetics

Congenital Microcoria: Clinical Features and Molecular Genetics

Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

Case Report: Papillary thyroid carcinoma in Goltz–Gorlin syndrome

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