11p14.1 microdeletions associated with ADHD, autism, developmental delay, and obesity

Shinawi, Marwan; Sahoo, Trilochan; Maranda, Bruno; Skinner, Steven A.; Skinner, Cindy; Chinault, Craig; Zascavage, Roxanne R.; Peters, Sarika U.; Patel, Ankita; Stevenson, Roger E.; Beaudet, Arthur L.

doi:10.1002/ajmg.a.33878

Cited by 86 publications

(68 citation statements)

References 47 publications

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“…Moreover, underlying the key role of the LIN7:IRSp53 association in neuritogenesis, our results suggest that neurodevelopmental disorders, such as human attentiondeficit/hyperactivity disorder (ADHD), recently associated with polymorphisms of LIN7 or IRSp53 or altered expression of LIN7 in humans (Lanktree et al, 2008;Ribasés et al, 2009;Zucker et al, 2010;Shinawi et al, 2011) may be due to unbalanced alterations in the expression of LIN7 and/or IRSp53 or to mutations that prevent their interaction.…”

Section: Discussionmentioning

confidence: 80%

“…In vertebrates, there are three genes, LIN7-A-B-C also named MALS/Veli-1-2-3, and alterations in these genes cause renal defects and synaptic dysfunctions (Olsen et al, 2007), and mice harbouring null mutations of all the three LIN7 isoforms die perinatally with respiratory problems and impaired synaptic transmission (Olsen et al, 2005). Moreover, polymorphisms and altered expression of LIN7 have been recently associated with human psychiatric conditions such as attention-deficit/ hyperactivity disorder (ADHD) and neurodegenerative diseases (Lanktree et al, 2008;Zucker et al, 2010;Shinawi et al, 2011). Interestingly, certain IRSp53 alleles in humans have also been linked to ADHD (Ribasés et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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LIN7 regulates the filopodia and neurite promoting activity of IRSp53

Crespi¹,

Ferrari²,

Lonati³

et al. 2012

Journal of Cell Science

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SummaryThe insulin receptor substrate protein of 53 kDa (IRSp53) is crucially involved in the formation of filopodia and neurites through mechanisms that have only partially been clarified. We have investigated the role of the small scaffold protein LIN7, which interacts with IRSp53. We found that formation of actin-filled protrusions in neuronal NSC34 cells and neurites in neuroblastoma N2A cells depends on motifs mediating the LIN7:IRSp53 association, as both the coexpression of LIN7 with IRSp53 or the expression of the L27-IRSp53 chimera (a fusion protein between IRSp53 and the LIN7L27 domain for plasma membrane protein complexes association) prevented actin-deficient protrusions induced by overexpressed IRSp53, and enhanced the formation of actin-filled protrusions. The regulatory role of LIN7 in IRSp53-mediated extension of filopodia in neuronal N2A cells was demonstrated by live-cell imaging experiments. Moreover, LIN7 silencing prevented the extension of filopodia and neurites, induced by ectopic expression of IRSp53 or serum starvation, respectively, in undifferentiated and differentiated N2A cells. The expression of full-length IRSp53 or the LIN7DPDZ mutant lacking the domain for association with IRSp53 was unable to restore neuritogenesis in LIN7-silenced cells. Conversely, defective neuritogenesis could be rescued by the expression of RNAi-resistant full-length LIN7 or chimeric L27-IRSp53. Finally, LIN7 silencing prevented the recruitment of IRSp53 in Triton X-100-insoluble complexes, otherwise occurring in differentiated cells. Collectively these data indicate that LIN7 is a novel regulator of IRSp53, and that the association of these proteins is required to promote the formation of actin-dependent filopodia and neurites.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

LIN7 regulates the filopodia and neurite promoting activity of IRSp53

Crespi¹,

Ferrari²,

Lonati³

et al. 2012

Journal of Cell Science

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“…al., 2010; Wentzel et al, 2010;Dasouki et al, 2011;Shinawi et al, 2011;Vergult et al, 2012;D'Angelo et al, 2013;Doco-Fenzy et al, 2014;Vuillaume et al, 2014].…”

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Two New Cases of 1p21.3 Deletions and an Unbalanced Translocation t(8;12) among Individuals with Syndromic Obesity

et al. 2015

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due to duplication of the GNB3 gene. Thus, our findings add to the existing literature on the clinical description of these new syndromes, providing additional support that these loci are associated with syndromic obesity. We suggest that heterozygous loss of MIR137 may contribute to obesity as well as ID and ASD. AbstractObesity is a highly heritable but genetically heterogeneous disorder. Various well-known microdeletion syndromes (e.g. 1p36, 2q37, 6q16, 9q34, 17p11.2) can cause this phenotype along with intellectual disability (ID) and other findings. Chromosomal microarrays have identified 'new' microdeletion/duplication syndromes often associated with obesity. We report on 2 unrelated patients with an overlapping region of deletion at 1p21.3p21.2, and a third patient with a de novo recurrent unbalanced translocation der(8)t(8; 12) (p23.1;p13.31), detected by 180K array CGH in a prospective cohort of syndromic obesity patients. Deletion of 1p21.3 is a rare condition, and there have been only 11 cases of the same recurrent translocation between chromosomes 8 and 12 [t(8; 12)] reported to date. The former has been associated with ID, autistic spectrum disorder (ASD) and mild dysmorphic features, and in 4 patients who were obese or had a tendency to obesity, a minimal overlapping region of 2 genes, DPYD and MIR137 , was detected; t(8; 12) has recently been recognized to cause a childhood obesity syndrome

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“…Recent studies reported that deletion of BDNF (brain-derived neurotrophic factor), which is present in 11p14.1, is attributable to the obesity found in WAGR syndrome (2). 11p14.1 microdeletions are associated with attention-deficit hyperactivity disorder, autism, developmental delay, and obesity in humans (10). PRRG4 (transmembrane ␥-carboxyglutamic acid protein 4) and SLC1A2 (solute carrier family 1 member 2), which have been reported to be deleted in some WAGR syndrome patients, may be implicated in autism (4).…”

mentioning

confidence: 99%