FMR1, FMR2, and SLITRK2 deletion inside a paracentric inversion involving bands Xq27.3–q28 in a male and his mother

Cavani, Simona; Prontera, Paolo; Grasso, Marina; Ardisia, Carmela; Malacarne, Michela; Gradassi, Cristina; Cecconi, Massimiliano; Mencarelli, Amedea; Donti, Emilio; Pierluigi, Mauro

doi:10.1002/ajmg.a.33515

Cited by 8 publications

(7 citation statements)

References 12 publications

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“…This simultaneously explained the ID and the presence of a chromosomal fragile site (31)(32)(33). Large deletions that include both AFF2 and the adjacent FMR1 gene result in a severe ID (34)(35)(36), whereas deletions of the AFF2 locus only present with autism and mild ID (37). A duplication of the AFF2 locus has also been reported in a young male with ID (38).…”

Section: Introductionmentioning

confidence: 87%

Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder

Mondal

Ramachandran

Patel

et al. 2012

Human Molecular Genetics

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Autism spectrum disorder (ASD) is a heterogeneous disorder with substantial heritability, most of which is unexplained. ASD has a population prevalence of one percent and affects four times as many males as females. Patients with fragile X E (FRAXE) intellectual disability, which is caused by a silencing of the X-linked gene AFF2, display a number of ASD-like phenotypes. Duplications and deletions at the AFF2 locus have also been reported in cases with moderate intellectual disability and ASD. We hypothesized that other rare X-linked sequence variants at the AFF2 locus might contribute to ASD. We sequenced the AFF2 genomic region in 202 male ASD probands and found that 2.5% of males sequenced had missense mutations at highly conserved evolutionary sites. When compared with the frequency of missense mutations in 5545 X chromosomes from unaffected controls, we saw a statistically significant enrichment in patients with ASD (OR: 4.9; P < 0.014). In addition, we identified rare AFF2 3' UTR variants at conserved sites which alter gene expression in a luciferase assay. These data suggest that rare variation in AFF2 may be a previously unrecognized ASD susceptibility locus and may help explain some of the male excess of ASD.

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Section: Introductionmentioning

confidence: 87%

Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder

Mondal

Ramachandran

Patel

et al. 2012

Human Molecular Genetics

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“…Slitrk proteins, members of the Slit and Trk-like (Slitrk) protein family, are type I transmembrane leucine-rich repeat (LRR) domain-containing proteins that are broadly expressed in the central nervous system and enriched at synapses. Interestingly, mutations in Slitrk genes have been associated with neuropsychiatric disorders (Abelson et al, 2005;Zuchner et al, 2006;Proenca et al, 2011;Piton et al, 2011;Shmelkov et al, 2010;Song et al, 2017;Cavani et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Opposite Control of Excitatory and Inhibitory Synapse Formation by Slitrk2 and Slitrk5 on Dopamine Neurons Modulates Hyperactivity Behavior

Salesse¹,

Charest²,

Doucet-Beaupré³

et al. 2020

Cell Reports

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Graphical Abstract Highlights d Lmx1a/b control Slitrk2 and Slitrk5 expression in midbrain dopamine neurons d Slitrk2 and Slitrk5 regulate excitatory and inhibitory synapse formation, respectively d Chronic inhibition of VTA neurons during development results in hyperactivity d Developmental changes in E/I balance on dopamine neurons lead to hyperlocomotion SUMMARY The neurodevelopmental origin of hyperactivity disorder has been suggested to involve the dopaminergic system, but the underlying mechanisms are still unknown. Here, transcription factors Lmx1a and Lmx1b are shown to be essential for midbrain dopaminergic (mDA) neuron excitatory synaptic inputs and dendritic development. Strikingly, conditional knockout (cKO) of Lmx1a/b in postmitotic mDA neurons results in marked hyperactivity. In seeking Lmx1a/b target genes, we identify positively regulated Slitrk2 and negatively regulated Slitrk5. These two synaptic adhesion proteins promote excitatory and inhibitory synapses on mDA neurons, respectively. Knocking down Slitrk2 reproduces some of the Lmx1a/b cKO cellular and behavioral phenotypes, whereas Slitrk5 knockdown has opposite effects. The hyperactivity caused by this imbalance in excitatory/inhibitory synaptic inputs on dopamine neurons is reproduced by chronically inhibiting the ventral tegmental area during development using pharmacogenetics. Our study shows that alterations in developing dopaminergic circuits strongly impact locomotor activity, shedding light on mechanisms causing hyperactivity behaviors.

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“…Whereas deletions within the FMR1 gene also have been recognized as causing FRAXA [Coffee et al, 2008] little is known about deletions of the FMR2 gene as potential cause of FRAXE in the absence of the trinucleotide expansion. Several reports on large deletions including the FMR1 , FMR2 , and other adjacent genes like IDS and SLITRK2 have been published [Timms et al, 1997; Moore et al, 1999; Fengler et al, 2002; Probst et al, 2007; Cavani et al, 2011]. However, reports on alterations affecting only the FMR2 gene are, to the extent of our knowledge, limited to descriptions of a balanced translocation having the breakpoint within the FMR2 gene [Honda et al, 2007] and two submicroscopic deletions which originally led to the cloning of the FMR2 gene [Gedeon et al, 1995; Gecz et al, 1996].…”

Section: Discussionmentioning

confidence: 99%

Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion

Stettner

Shoukier

Höger

et al. 2011

American J of Med Genetics Pt A

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Alterations of the Fragile Mental Retardation 2 gene (FMR2, synonym AFF2) can result in non-specific, mild to borderline X-linked intellectual disability (XLID), and behavioral problems. The well-known molecular pathomechanism of this condition, also referred to as FRAXE, is a (CCG)(n) trinucleotide repeat expansion which leads to silencing of the FMR2 gene. However, deletions within the FMR2 gene may also be causative of the disorder. Here, we report on two brothers diagnosed with FRAXE in whom a small deletion in the FMR2 gene was detected by whole genome array comparative genomic hybridization (CGH). The deletion was also present in their clinically healthy mother and maternal uncle who was similarly affected, but not in a healthy older brother of the two patients. Our observation demonstrates that FMR2 gene deletions may contribute to the FRAXE phenotype. Therefore, we suggest that screening for FMR2 gene deletions using array CGH should be considered in patients with non-specific XLID and absent trinucleotide expansion.

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FMR1, FMR2, and SLITRK2 deletion inside a paracentric inversion involving bands Xq27.3–q28 in a male and his mother

Cited by 8 publications

References 12 publications

Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder

Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder

Opposite Control of Excitatory and Inhibitory Synapse Formation by Slitrk2 and Slitrk5 on Dopamine Neurons Modulates Hyperactivity Behavior

Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion

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