Lissencephaly, X-Linked, 2

Last update 01 Nov 2024

Basic Info

Synonyms

LISSENCEPHALY, X-LINKED, 2, LISSENCEPHALY, X-LINKED, WITH AMBIGUOUS GENITALIA, LISX2

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Introduction

A severe neurological disorder that only manifests in genotypic males and includes lissencephaly with posterior-to-anterior gradient and only moderate increase in thickness of the cortex, absent corpus callosum, neonatal-onset severe epilepsy, hypothalamic dysfunction including defective temperature regulation, and ambiguous genitalia with micropenis and cryptorchidism.

100 Clinical Results associated with Lissencephaly, X-Linked, 2

100 Translational Medicine associated with Lissencephaly, X-Linked, 2

0 Patents (Medical) associated with Lissencephaly, X-Linked, 2

Literatures (Medical) associated with Lissencephaly, X-Linked, 2

12 Sep 2024·Endocrine Reviews

The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism

Review

Author: Beckers, Albert ; Daly, Adrian F

AbstractPituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of patients with pituitary gigantism have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH-releasing hormone is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G-protein–coupled receptor, GPR101. This leads to the formation of a neo-TAD in which GPR101 overexpression is driven by ectopic enhancers (“TADopathy”). X-LAG has been seen in 3 families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1, and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.

01 Mar 2024·Journal of Molecular Graphics and Modelling

GPR101: Modeling a constitutively active receptor linked to X-linked acrogigantism

Article

Author: Stahr, Lea G ; Trivellin, Giampaolo ; Stratakis, Constantine A ; Costanzi, Stefano

GPR101 is a G protein-coupled receptor (GPCR) implicated in a rare form of genetic gigantism known as X-linked acrogigantism, or X-LAG. In particular, X-LAG patients harbor microduplications in the long arm of the X-chromosome that invariably include the GPR101 gene. Duplications of the GPR101 gene lead to the formation of a new chromatin domain that causes over-expression of the receptor in the pituitary tumors of the patients. Notably, GPR101 is a constitutively active receptor, which stimulates cells to produce the second messenger cyclic AMP (cAMP) in the absence of ligands. Moreover, GPR101 was recently reported to constitutively activate not only the cAMP pathway via G_s, but also other G protein subunits (G_q/11 and G_12/13). Hence, chemicals that block the constitutive activity of GPR101, known as inverse agonists, have the potential to be useful for the development of pharmacological tools for the treatment of X-LAG. In this study, we provide structural insights into the putative structure of GPR101 based on in-house built homology models, as well as third party models based on the machine learning methods AlphaFold and AlphaFold-Multistate. Moreover, we report a molecular dynamics study, meant to further probe the constitutive activity of GPR101. Finally, we provide a structural comparison with the closest GPCRs, which suggests that GPR101 does not share their natural ligands. While this manuscript was under review, cryo-electron microscopy structures of GPR101 were reported. These structures are expected to enable computer-aided ligand discovery efforts targeting GPR101.

10 Sep 2023·Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics

[Analysis of ARX gene variant in a child with X-linked lissencephaly with abnormal genitalia].

Article

Author: Wang, Huijuan ; Shang, Lihong ; Tian, Yuan ; Xu, Falin ; Fan, Xufang ; Wang, Jinguang ; Guo, Jiajia ; Zhang, Xiaoli

OBJECTIVETo explore the clinical characteristics and genetic basis for a child with X-linked lissencephaly with abnormal genitalia (XLAG).METHODSA child with XLAG who had presented at the Third Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to high-throughput sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the result was analyzed by using bioinformatic software.RESULTSThe child was found to have harbored a hemizygous c.945_948del variant in exon 2 of the ARX gene, which as a frameshifting variant has resulted in a truncated protein. His mother was found to be heterozygous for the variant, whilst his father was of wild type. The variant was unreported previously.CONCLUSIONThe hemizygous c.945_948del variant of the ARX gene probably underlay the XLAG in this patient. Above finding has provided a basis for the diagnosis and genetic counseling for this family.

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Lissencephaly, X-Linked, 2

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