Homozygous CDH2 variant may be associated with hypopituitarism without neurological disorders

Context Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition. Objectives The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant. Design Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing. Results One female patient with deficiencies in growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with variant CDH2 or non-transfected. Conclusion A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations. Significance statement A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in CDH2 were identified in 145 hypopituitarism patients.

[1]  Adam Shellard,et al.  Collective durotaxis along a self-generated stiffness gradient in vivo , 2021, Nature.

[2]  O. Birk,et al.  CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice , 2021, Nature Communications.

[3]  S. Marie,et al.  SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in São Paulo , 2020, Clinics.

[4]  Elizabeth L. Fieg,et al.  De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects. , 2019, American journal of human genetics.

[5]  K. Tachibana.  N-cadherin-mediated aggregate formation; cell detachment by Trypsin-EDTA loses N-cadherin and delays aggregate formation. , 2019, Biochemical and biophysical research communications.

[6]  K. Mrozik,et al.  N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer , 2018, BMC Cancer.

[7]  J. Sanes,et al.  Cadherins Interact With Synaptic Organizers to Promote Synaptic Differentiation , 2018, Front. Mol. Neurosci..

[8]  Han Zhou,et al.  Role of epithelial-mesenchymal transition markers E-cadherin, N-cadherin, β-catenin and ZEB2 in laryngeal squamous cell carcinoma , 2018, Oncology letters.

[9]  Riitta Veijola,et al.  Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis , 2017, Nature Communications.

[10]  S. Davis,et al.  Canonical WNT Signaling Regulates the Pituitary Organizer and Pituitary Gland Formation , 2017, Endocrinology.

[11]  S. Etienne-Manneville,et al.  Single and collective cell migration: the mechanics of adhesions , 2017, Molecular biology of the cell.

[12]  D. Y. Sunaga,et al.  Exomic variants of an elderly cohort of Brazilians in the ABraOM database , 2017, Human mutation.

[13]  H. Shintaku,et al.  A Japanese Family with Central Hypothyroidism Caused by a Novel IGSF1 Mutation. , 2016, Thyroid : official journal of the American Thyroid Association.

[14]  Ryan E. Mills,et al.  Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era. , 2016, Endocrine reviews.

[15]  Brent W. Weyers,et al.  Deletion of the cytoplasmic domain of N-cadherin reduces, but does not eliminate, traction force-transmission. , 2016, Biochemical and biophysical research communications.

[16]  S. Camper,et al.  PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells , 2016, eLife.

[17]  F. Prodam,et al.  Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort , 2015, Clinical endocrinology.

[18]  K. Kaibuchi,et al.  Radial Glial Cell–Neuron Interaction Directs Axon Formation at the Opposite Side of the Neuron from the Contact Site , 2015, The Journal of Neuroscience.

[19]  B. Mendonca,et al.  Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: a long term follow-up of patients from a single center , 2015, Pituitary.

[20]  K. Hashimoto,et al.  N-cadherin-based adherens junction regulates the maintenance, proliferation, and differentiation of neural progenitor cells during development , 2015, Cell adhesion & migration.

[21]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[22]  D. Tang,et al.  Recruitment of β-Catenin to N-Cadherin Is Necessary for Smooth Muscle Contraction* , 2015, The Journal of Biological Chemistry.

[23]  Magalie S Leduc,et al.  Molecular findings among patients referred for clinical whole-exome sequencing. , 2014, JAMA.

[24]  E. Stupka,et al.  ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. , 2013, Brain : a journal of neurology.

[25]  Eric Theveneau,et al.  Chase-and-run between adjacent cell populations promotes directional collective migration , 2013, Nature Cell Biology.

[26]  Julian R. E. Davis,et al.  Wnt signalling in pituitary development and tumorigenesis. , 2013, Endocrine-related cancer.

[27]  A. Chenn,et al.  AKT activation by N-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development , 2013, Neural Development.

[28]  E. Ginns,et al.  Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes , 2013, European Journal of Human Genetics.

[29]  R. Brewster,et al.  N-cadherin–mediated cell adhesion restricts cell proliferation in the dorsal neural tube , 2011, Molecular biology of the cell.

[30]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[31]  L. Raetzman,et al.  N-cadherin loss in POMC-expressing cells leads to pituitary disorganization. , 2011, Molecular endocrinology.

[32]  J. Levinson,et al.  N-cadherin and Neuroligins Cooperate to Regulate Synapse Formation in Hippocampal Cultures , 2010, Journal of Biological Chemistry.

[33]  Chuangye Yan,et al.  Single Amino Acid Alteration between Valine and Isoleucine Determines the Distinct Pyrabactin Selectivity by PYL1 and PYL2* , 2010, The Journal of Biological Chemistry.

[34]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[35]  M. Pierce,et al.  Regulation of Homotypic Cell-Cell Adhesion by Branched N-Glycosylation of N-cadherin Extracellular EC2 and EC3 Domains* , 2009, The Journal of Biological Chemistry.

[36]  Zhaoming Lu,et al.  An essential role for N-cadherin and beta-catenin for progression in tongue squamous cell carcinoma and their effect on invasion and metastasis of Tca8113 tongue cancer cells. , 2009, Oncology reports.

[37]  D. Ghosh,et al.  Discovery of transcriptional regulators and signaling pathways in the developing pituitary gland by bioinformatic and genomic approaches. , 2009, Genomics.

[38]  Christopher R. Jacobs,et al.  Non-Canonical Wnt Signaling and N-Cadherin Related β-Catenin Signaling Play a Role in Mechanically Induced Osteogenic Cell Fate , 2009, PloS one.

[39]  A. Kispert,et al.  WNT signaling affects gene expression in the ventral diencephalon and pituitary gland growth , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[40]  N. Chen,et al.  Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway. , 2005, Molecular biology of the cell.

[41]  D. Nass,et al.  The cell adhesion molecules N-cadherin and neural cell adhesion molecule regulate human growth hormone: a novel mechanism for regulating pituitary hormone secretion. , 2003, The Journal of clinical endocrinology and metabolism.

[42]  M. S. Steinberg,et al.  Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants. , 2003, Developmental biology.

[43]  Wayne A. Hendrickson,et al.  Structure-Function Analysis of Cell Adhesion by Neural (N-) Cadherin , 1998, Neuron.

[44]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[45]  M. Takeichi,et al.  Immunological detection of cell surface components related with aggregation of Chinese hamster and chick embryonic cells. , 1979, Developmental biology.

[46]  M. Takeichi,et al.  Functional correlation between cell adhesive properties and some cell surface proteins , 1977, The Journal of cell biology.

[47]  M. Takeichi,et al.  Roles of magnesium and calcium ions in cell-to-substrate adhesion. , 1972, Experimental cell research.

[48]  J M Tanner,et al.  Variations in the Pattern of Pubertal Changes in Boys , 1970, Archives of disease in childhood.

[49]  J M Tanner,et al.  Variations in pattern of pubertal changes in girls. , 1969, Archives of disease in childhood.

[50]  J. Tanner,et al.  Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children, 1965. I. , 1966, Archives of disease in childhood.

[51]  B. Ellsworth,et al.  Pituitary gland development and disease: from stem cell to hormone production. , 2013, Current topics in developmental biology.

[52]  L. Raetzman,et al.  Premature differentiation and aberrant movement of pituitary cells lacking both Hes1 and Prop1. , 2009, Developmental biology.

[53]  S. Parlee,et al.  This Work Is Licensed under a Creative Commons Attribution-noncommercial 4.0 International License , 2022 .