Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis

Esch, Hilde Van; Hollanders, Karolien; Badisco, Liesbeth; Melotte, Cindy; Hummelen, Paul Van; Vermeesch, Joris Robert; Devriendt, Koen; Marynen, Peter; Froyen, Guy

doi:10.1093/hmg/ddi186

Cited by 109 publications

(103 citation statements)

References 25 publications

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“…Although individuals with this deletion usually show normal development, some also present with intellectual disability and susceptibility to ADHD, autism and social communication deficits. 18,19 Therefore, we cannot exclude the fact that, besides ichthyosis, this deletion additionally contributes to the developmental and behavior phenotype. One should note that the mother of the patient carries the same deletion without features of ichthyosis.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

et al. 2010

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Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

et al. 2010

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“…Previous studies have shown that there are more nonsynonymous than synonymous substitutions between genes VCX and VCY (Lahn and Page 2000). VCX is expressed exclusively in germ-line cells and, while the function of VCX is not known, studies have suggested an intriguing association with cognitive development (Van Esch et al 2005). Though it is not significant, it is nonetheless interesting to note the excess of adaptively evolving genes we found that are involved in neuronal and cognitive functions, as well as being used in response to social stresses among primates (Sapolsky 2005).…”

Section: Genes With a History Of Adaptive Evolution Along The Human Lmentioning

confidence: 99%

Adaptive evolution of young gene duplicates in mammals

Demuth²,

et al. 2009

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Duplicate genes act as a source of genetic material from which new functions arise. They exist in large numbers in every sequenced eukaryotic genome and may be responsible for many differences in phenotypes between species. However, recent work searching for the targets of positive selection in humans has largely ignored duplicated genes due to complications in orthology assignment. Here we find that a high proportion of young gene duplicates in the human, macaque, mouse, and rat genomes have experienced adaptive natural selection. Approximately 10% of all lineage-specific duplicates show evidence for positive selection on their protein sequences, larger than any reported amount of selection among single-copy genes in these lineages using similar methods. We also find that newly duplicated genes that have been transposed to new chromosomal locations are significantly more likely to have undergone positive selection than the ancestral copy. Human-specific duplicates evolving under adaptive natural selection include a surprising number of genes involved in neuronal and cognitive functions. Our results imply that genome scans for selection that ignore duplicated loci are missing a large fraction of all adaptive substitutions. The results are also in agreement with the classical model of evolution by gene duplication, supporting a common role for neofunctionalization in the long-term maintenance of gene duplicates.[Supplemental material is available online at www.genome.org.]Recently duplicated loci suffer one of two long-term fates: maintenance or loss (Ohno 1970;Walsh 1995). While pseudogenization is the more likely fate of recently duplicated genes, many models have been proposed that could lead to the long-term maintenance of multiple paralogs (Spofford 1969;Ohno 1970;Dykhuizen and Hartl 1980;Hughes 1994;Force et al. 1999;Stoltzfus 1999). The maintenance of duplicates can be a by-product of neutral evolution (Dykhuizen and Hartl 1980;Force et al. 1999;Stoltzfus 1999), or there can be adaptive substitutions either during (Spofford 1969;Ohno 1970) or after (Ohno 1970Hughes 1994) the fixation of the duplicated locus. Previous studies have found signatures of adaptive evolution among individual duplicated genes, suggesting that selection for new functions (''neofunctionalization'') is the mechanism acting to retain new paralogs (Zhang et al. 1998;Merritt and Quattro 2001;Betran and Long 2003;Moore and Purugganan 2003;Rodriguez-Trelles et al. 2003;Thornton and Long 2005). While these studies support the neofunctionalization model, the genome-wide proportion of all duplicates fixed and maintained by natural selection is still not known (Hahn 2009).Gene duplication supplies the raw material necessary to evolve novel functions and is therefore a source of adaptive change. Previous studies in mammals have searched for positively selected genes in the hope of identifying the nucleotide substitutions that underlie phenotypic divergence between species, but these genome-wide scans have intentionally ignored duplicated loci ...

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“…The finding of mental retardation in these reported cases with a contiguous gene deletion syndrome and the mapping of the deletions established the presence of a locus for mental retardation between ARSE and STS. Recent studies have implicated VCXA (also known as VCX 3A) Van Esch et al, 2005;Hosomi et al, 2007). However, this has been contradicted by the mapping of the deletion in a large cohort of patients with isolated STS deficiency, which showed that in a significant proportion the deletion included the VCX 3A and VCX genes .…”

Section: Introductionmentioning

confidence: 99%

Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols

et al. 2009

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ObjectiveTo ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome.MethodsWe reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy.ResultsThirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%).ConclusionThe clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus. Copyright © 2009 John Wiley & Sons, Ltd.

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Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis

Cited by 109 publications

References 25 publications

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

Adaptive evolution of young gene duplicates in mammals

Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols

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