<i>KCNA4</i>deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability

Kaya, Namik; Alsagob, Maysoon; D’Adamo, Maria Cristina; Al-Bakheet, Albandary; Hasan, Sonia; Muccioli, Maria; Almutairi, Faten; Almass, Rawan; Aldosary, Mazhor; Monies, Dorota; Mustafa, Osama M.; Al-Younes, Banan; Kenana, Rosan; Al-Zahrani, Jawaher; Naim, Ewa A.; BinHumaid, Faisal S.; Qari, Alya; Almutairi, Fatema; Meyer, Brian F.; Plageman, Timothy F.; Pessia, Mauro; Çolak, Dilek; Al‐Owain, Mohammed

doi:10.1136/jmedgenet-2015-103637

Cited by 22 publications

(17 citation statements)

References 62 publications

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“…Several other candidates, such as CACNB2 [ 54 ], CDH8 [ 55 ], HERC1 [ 56 ], KCTD3 [ 57 ], KIF13B [ 58 ], SERINC2 [ 59 ], and SLC39A11 [ 60 ] have been associated with ASD. Some candidates have been linked to intellectual disability (ID), such as CRBN [ 61 ], GPKOW [ 62 ], HERC1 [ 56 ] and KCNA4 [ 63 ], or to other behavioral disorders, such as CDC42EP4 [ 64 ] and SLITRK5 [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

2018

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Devil Facial Tumor Disease (DFTD) is an aggressive cancer notorious for its rare etiology and its impact on Tasmanian devil populations. Two regions underlying an evolutionary response to this cancer were recently identified using genomic time-series pre- and post-DTFD arrival. Here, we support that DFTD shaped the genome of the Tasmanian devil in an even more extensive way than previously reported. We detected 97 signatures of selection, including 148 protein coding genes having a human orthologue, linked to DFTD. Most candidate genes are associated with cancer progression, and an important subset of candidate genes has additional influence on social behavior. This confirms the influence of cancer on the ecology and evolution of the Tasmanian devil. Our work also demonstrates the possibility to detect highly polygenic footprints of short-term selection in very small populations.

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Section: Resultsmentioning

confidence: 99%

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

2018

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“…While many of the genes enriched for D1+ and D2+ expression are not exclusive to the striatum and are more broadly expressed (as demonstrated by the enrichment signal at the lowest specificity threshold), the striatum has been implicated in ID and autism pathology by numerous studies 88-97 . The striatum is particularly compelling as it has been linked to repetitive behaviors 88 core to the autism phenotype and also to genes known to be involved in DD, including CHD8 , SHANK3 , FOXP2 , and KCNA4 89,90,93,96,97 . While the striatum is most strongly linked to autism core phenotypes, our observation of enrichment in a more general DD cohort suggests that, while the general bias of cortex genes to ID and striatum genes to ASD 92 still holds, the diverse expression patterns of genes across the brain at complex developmental time points may have substantial functional overlap among subtypes of NDDs that will require deep phenotyping and imaging to tease apart.…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity

et al. 2018

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We combined de novo mutation (DNM) data from 10,927 cases of developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive mutations. Of these genes, 124 reach exome-wide significance (p < 5 × 10 −7 ) for DNM. Intersecting these results with copy number variation morbidity data shows an enrichment for genomic disorder regions (30/253, LR+ 1.85, p = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (e.g., KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum.

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“…Their altered expression can affect synaptic transmission of Area X neurons. KCNA4 encodes a voltage-gated potassium channel ( Ovsepian et al, 2016 ), and mutations in KCNA4 have been identified in patients exhibiting linguistic disabilities, attention deficit hyperactivity disroder (ADHD), and cognitive impairments ( Kaya et al, 2016 ). MMP2, a member of the matrix metalloproteinase family, plays critical roles in synaptogenesis, dendrite remodeling, and neurogenesis ( Fujioka et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

miR-9 regulates basal ganglia-dependent developmental vocal learning and adult vocal performance in songbirds

Shi

Piccus

Zhang

et al. 2018

eLife

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miR-9 is an evolutionarily conserved miRNA that is abundantly expressed in Area X, a basal ganglia nucleus required for vocal learning in songbirds. Here, we report that overexpression of miR-9 in Area X of juvenile zebra finches impairs developmental vocal learning, resulting in a song with syllable omission, reduced similarity to the tutor song, and altered acoustic features. miR-9 overexpression in juveniles also leads to more variable song performance in adulthood, and abolishes social context-dependent modulation of song variability. We further show that these behavioral deficits are accompanied by downregulation of FoxP1 and FoxP2, genes that are known to be associated with language impairments, as well as by disruption of dopamine signaling and widespread changes in the expression of genes that are important in circuit development and functions. These findings demonstrate a vital role for miR-9 in basal ganglia function and vocal communication, suggesting that dysregulation of miR-9 in humans may contribute to language impairments and related neurodevelopmental disorders.

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KCNA4deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability

Abstract: (Kv1.4) is implicated in a novel syndrome characterised by striatal thinning, congenital cataract and attention deficit hyperactivity disorder. Our study highlights potassium channels' role in ocular and neuronal genetics.

Cited by 22 publications

References 62 publications

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity

miR-9 regulates basal ganglia-dependent developmental vocal learning and adult vocal performance in songbirds

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