A Number of Schizencephaly Patients Including 2 Brothers Are Heterozygous for Germline Mutations in the Homeobox Gene EMX2

Faiella, A.; Brunelli, Silvia; Granata, Tiziana; D’Incerti, Ludovico; Cardini, Roldano; Lenti, C; Battaglia, Giorgio; Boncinelli, Edoardo

doi:10.1159/000484761

Cited by 73 publications

(44 citation statements)

References 6 publications

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“…Two other patients carried a heterozygous splice mutation, and altered splicing was demonstrated in transfected 3T3 cells. The same group reported de novo EMX2 mutations in a second cohort of six patients in 1997 (Faiella et al 1997). In contrast, negative results of an EMX2 mutation analysis in two additional patient cohorts have been reported recently and extensively discussed (Tietjen et al 2007; Merello et al 2008).…”

Section: Introductionmentioning

confidence: 90%

Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly

et al. 2010

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Schizencephaly (SCH) is a clinically and etiologically heterogeneous cerebral malformation presenting as unilateral or bilateral hemispheric cleft with direct connection between the inner and outer liquor spaces. The SCH cleft is usually lined by gray matter, which appears polymicrogyric implying an associated impairment of neuronal migration. The majority of SCH patients are sporadic, but familial SCH has been described. An initial report of heterozygous mutations in the homeobox gene EMX2 could not be confirmed in 52 patients investigated in this study in agreement with two independent SCH patient cohorts published previously. SCH frequently occurs with additional cerebral malformations like hypoplasia or aplasia of the septum pellucidum or optic nerve, suggesting the involvement of genes important for the establishment of midline forebrain structures. We therefore considered holoprosencephaly (HPE)-associated genes as potential SCH candidates and report for the first time heterozygous mutations in SIX3 and SHH in a total of three unrelated patients and one fetus with SCH; one of them without obvious associated malformations of midline forebrain structures. Three of these mutations have previously been reported in independent patients with HPE. SIX3 acts directly upstream of SHH, and the SHH pathway is a key regulator of ventral forebrain patterning. Our data indicate that in a subset of patients SCH may develop as one aspect of a more complex malformation of the ventral forebrain, directly result from mutations in the SHH pathway and hence be considered as yet another feature of the broad phenotypic spectrum of holoprosencephaly.

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Section: Introductionmentioning

confidence: 90%

Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly

et al. 2010

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“…Examples of genes with critical roles in arealization include Emx2 , Pax6 , and COUP-TFI ( Nr2f1 ) (Krubitzer, 2007). Not surprisingly, variation in some of these genes leads to cognitive deficits including schizencephaly ( EMX2 ) (Brunelli et al, 1996; Faiella et al, 1997), or cerebellar ataxia and intellectual disability (Gillespie syndrome; PAX6 ) (Graziano et al, 2007; Ticho et al, 2006). A better understanding of the genes important for arealization in mammalian brain evolution should provide insight into the gene networks underlying higher cognition.…”

Section: Evo-genomentioning

confidence: 99%

Human Brain Evolution: Harnessing the Genomics (R)evolution to Link Genes, Cognition, and Behavior

Konopka

Geschwind

2010

Neuron

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The evolution of the human brain has resulted in numerous specialized features including higher cognitive processes, such as language. The combination of our newfound communication expertise together with the process of transgenerational evolution at the epigenetic level has led to an exponential increase in human knowledge and abilities. In balance with these beneficent attainments though, the human brain has also acquired vulnerabilities to neuropsychiatric and neurodegenerative diseases, which reflect genetic and environmental factors. To understand the mechanisms of this disease susceptibility, a deeper appreciation of the developmental processes and their relationship to underlying features of brain evolution will be necessary. Knowledge of whole genome sequence and structural variation via high throughput sequencing technology provides an unprecedented opportunity to view human evolution at high resolution. However, phenotype discovery is a critical component of these endeavors and the use of non-traditional model organisms will also be critical for piecing together a complete picture. Ultimately, the union of developmental studies of the brain with studies of unique phenotypes in a myriad of species will result in a more thorough model of the groundwork the human brain built upon. Furthermore, these integrative approaches should provide important insights into human diseases.

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“…113 Heterozygous mutations in the homeobox gene EMX2 on chromosome 10q26.1 were reported in some sporadic and familial patients with schizencephaly. [114][115][116] Although the mutations are presumed to be autosomal dominant, the pattern of inheritance remains unclear. A causative role of EMX2 in the development of schizencephaly could not be reproduced by other research groups, 5 suggesting genetic heterogeneity or the involvement of modifying factors.…”

Section: Schizencephaly and Mutations In Emx2mentioning

confidence: 99%

Genetics of the polymicrogyria syndromes

Jansen

Andermann²

2005

Journal of Medical Genetics

147

132

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A Number of Schizencephaly Patients Including 2 Brothers Are Heterozygous for Germline Mutations in the Homeobox Gene EMX2

Cited by 73 publications

References 6 publications

Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly

Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly

Human Brain Evolution: Harnessing the Genomics (R)evolution to Link Genes, Cognition, and Behavior

Genetics of the polymicrogyria syndromes

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