Xq27.1 Duplication Encompassing &lt;b&gt;&lt;i&gt;SOX3&lt;/i&gt;&lt;/b&gt;: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date – A Large Case Series of Unrelated Patients and a Literature Review

Arya, Vivek; Chawla, Garima; Nambisan, Aparna K.R.; Muhi-Iddin, Nadia; Vamvakiti, Ekaterini; Ajzensztejn, Michal; Hulse, Tony; Pinto, Clare Ferreira; Lahiri, Nayana; Bint, Susan; Buchanan, Charles; Kapoor, Ritika R

doi:10.1159/000503784

Cited by 16 publications

(21 citation statements)

References 21 publications

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“…Contribution of SOX genes to NDDs is still not clear. Both deletions and duplications of SOX3 gene were detected in patients with intellectual disability (Stevanovic et al, 1993;Laumonnier et al, 2002;Helle et al, 2013;Stagi et al, 2014;Arya et al, 2019). Also, SOX3 missense variant was detected in proband with mild intellectual disability (Jelsig et al, 2018).…”

Section: Sox Transcription Factors and Neurodevelopmental Disordersmentioning

confidence: 96%

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Stevanović

Drakulić

Lazic

et al. 2021

Front. Mol. Neurosci.

104

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The SOX proteins belong to the superfamily of transcription factors (TFs) that display properties of both classical TFs and architectural components of chromatin. Since the cloning of the Sox/SOX genes, remarkable progress has been made in illuminating their roles as key players in the regulation of multiple developmental and physiological processes. SOX TFs govern diverse cellular processes during development, such as maintaining the pluripotency of stem cells, cell proliferation, cell fate decisions/germ layer formation as well as terminal cell differentiation into tissues and organs. However, their roles are not limited to development since SOX proteins influence survival, regeneration, cell death and control homeostasis in adult tissues. This review summarized current knowledge of the roles of SOX proteins in control of central nervous system development. Some SOX TFs suspend neural progenitors in proliferative, stem-like state and prevent their differentiation. SOX proteins function as pioneer factors that occupy silenced target genes and keep them in a poised state for activation at subsequent stages of differentiation. At appropriate stage of development, SOX members that maintain stemness are down-regulated in cells that are competent to differentiate, while other SOX members take over their functions and govern the process of differentiation. Distinct SOX members determine down-stream processes of neuronal and glial differentiation. Thus, sequentially acting SOX TFs orchestrate neural lineage development defining neuronal and glial phenotypes. In line with their crucial roles in the nervous system development, deregulation of specific SOX proteins activities is associated with neurodevelopmental disorders (NDDs). The overview of the current knowledge about the link between SOX gene variants and NDDs is presented. We outline the roles of SOX TFs in adult neurogenesis and brain homeostasis and discuss whether impaired adult neurogenesis, detected in neurodegenerative diseases, could be associated with deregulation of SOX proteins activities. We present the current data regarding the interaction between SOX proteins and signaling pathways and microRNAs that play roles in nervous system development. Finally, future research directions that will improve the knowledge about distinct and various roles of SOX TFs in health and diseases are presented and discussed.

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Section: Sox Transcription Factors and Neurodevelopmental Disordersmentioning

confidence: 96%

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Stevanović

Drakulić

Lazic

et al. 2021

Front. Mol. Neurosci.

104

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“…Many genes located at Xq22.3q27.2 are widely expressed in the CNS and were previously associated with syndromic/non-syndromic X-linked ID, such as ALG13, PAK3, THOC2, GRIA3, STAG2, OCRL1, AIFM1, PHF6, RMBX, SOX3, LAMP2, CUL4B, and UBE2A [ 54 , 55 ]. Moreover, patients with duplicated regions that encompass the X-linked genes SOX3, STAG2, AIFM1, GRIA3, PAK3, and OCRL exhibit ID [ 22 , 23 , 24 , 25 , 26 , 56 , 57 , 58 ]. Moreover, six genes from the duplicated region 18p11.32-p11.21 are highly expressed in several regions of the CNS, from which three of them (LAMA1, MYOM1, and TGIF1) were duplicated in individuals with ID [ 18 , 19 , 20 ].…”

Section: Resultsmentioning

confidence: 99%

Shared Neurodevelopmental Perturbations Can Lead to Intellectual Disability in Individuals with Distinct Rare Chromosome Duplications

Corrêa

Santos-Rebouças

Mayndra³

et al. 2021

Genes

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Chromosomal duplications are associated with a large group of human diseases that arise mainly from dosage imbalance of genes within the rearrangements. Phenotypes range widely but are often associated with global development delay, intellectual disability, autism spectrum disorders, and multiple congenital abnormalities. How different contiguous genes from a duplicated genomic region interact and dynamically affect the expression of each other remains unclear in most cases. Here, we report a genomic comparative delineation of genes located in duplicated chromosomal regions 8q24.13q24.3, 18p11.32p11.21, and Xq22.3q27.2 in three patients followed up at our genetics service who has the intellectual disability (ID) as a common phenotype. We integrated several genomic data levels by identification of gene content within the duplications, protein-protein interactions, and functional analysis on specific tissues. We found functional relationships among genes from three different duplicated chromosomal regions, reflecting interactions of protein-coding genes and their involvement in common cellular subnetworks. Furthermore, the sharing of common significant biological processes associated with ID has been demonstrated between proteins from the different chromosomal regions. Finally, we elaborated a shared model of pathways directly or indirectly related to the central nervous system (CNS), which could perturb cognitive function and lead to ID in the three duplication conditions.

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“… Hydrocephalus [ 39 ] F F hydrocephalus [ 40 ] III.2 F SS/GR [ 40 ] II.2 F SS/GR [ 40 ] III.4 F SS/GR [ 32 ] I M FTT Micropenis, hypoplastic scrotum GH, LH/FSH, TSH, ACTH Jaundice, hypoglycemia APH, EPP [ 32 ] II M SS/GR Micropenis and STV GH, ACTH, TSH, LH/FSH Hypoglycemia ACC, hydrocephalus [ 32 ] III M SS/GR Slender phallus and STV LH/FSH Thin CC, hydrocephalus [ 32 ] IV M …”

Section: Resultsmentioning

confidence: 99%

“…Duplications including SOX3 have been associated with variable clinical phenotypes, including X-linked intellectual disability (ID), GHD, X-linked hypopituitarism (XH), SRY-negative 46,XX disorders of sex development (DSD) and neural tube defects (NTD) [27][28][29][30][31][32][33]. The severity of the phenotype is not dependent on the size of the duplication.…”

Section: Discussionmentioning

confidence: 99%

Congenital hypopituitarism in two brothers with a duplication of the ‘acrogigantism gene’ GPR101: clinical findings and review of the literature

et al. 2020

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Purpose Congenital hypopituitarism (CH) can cause significant morbidity or even mortality. In the majority of patients, the etiology of CH is unknown. Understanding the etiology of CH is important for anticipation of clinical problems and for genetic counselling. Our previous studies showed that only a small proportion of cases have mutations in the known ‘CH genes’. In the current project, we present the results of SNP array based copy number variant analysis in a family with unexplained congenital hypopituitarism. Methods DNA samples of two affected brothers with idiopathic CH and their mother were simultaneously analyzed by SNP arrays for copy number variant analysis and Whole Exome Sequencing (WES) for mutation screening. DNA of the father was not available. Results We found a 6 Mb duplication including GPR101 and SOX3 on the X-chromosome (Xq26.2-q27.1) in the two siblings and their mother, leading to 2 copies of this region in the affected boys and 3 copies in the mother. Duplications of GPR101 are associated with X-linked acrogigantism (the phenotypic ‘opposite’ of the affected brothers), whereas alterations in SOX3 are associated with X-linked hypopituitarism. Conclusion In our patients with hypopituitarism we found a 6 Mb duplication which includes GPR101, a gene associated with X- linked gigantism, and SOX3, a gene involved in early pituitary organogenesis that is associated with variable degrees of hypopituitarism. Our findings show that in duplications containing both GPR101 and SOX3, the growth hormone deficiency phenotype is dominant. This suggests that, if GPR101 is duplicated, it might not be expressed phenotypically when early patterning of the embryonic pituitary is affected due to SOX3 duplication. These results, together with the review of the literature, shed a new light on the role of GPR101 and SOX3 in pituitary function.

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Xq27.1 Duplication Encompassing <b><i>SOX3</i></b>: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date – A Large Case Series of Unrelated Patients and a Literature Review

Cited by 16 publications

References 21 publications

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

Shared Neurodevelopmental Perturbations Can Lead to Intellectual Disability in Individuals with Distinct Rare Chromosome Duplications

Congenital hypopituitarism in two brothers with a duplication of the ‘acrogigantism gene’ GPR101: clinical findings and review of the literature

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