Ancestral Variations of the PCDHG Gene Cluster Predispose to Dyslexia in a Multiplex Family

Naskar, Teesta; Faruq, Mohammed; Banerjee, Priyajit; Khan, Massarat; Midha, Rashi; Kumari, Renu; Devasenapathy, Subhashree; Prajapati, Bharat; Sengupta, Sanghamitra; Jain, Deepti; Mukerji, Mitali; Singh, Nandini Chatterjee; Sinha, Subrata

doi:10.1016/j.ebiom.2017.12.031

Cited by 12 publications

(8 citation statements)

References 66 publications

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“…Members of the cadherin superfamily have emerged as key contributors to neurodevelopmental disorders, including autism, schizophrenia, bipolar disease, and intellectual disability (60)(61)(62). We have shown that Dscam can regulate the function of cadherins and protocadherins, making it a candidate target for these disabilities.…”

Section: Discussionmentioning

confidence: 99%

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members

Garrett

Khalil

Walton

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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During neural development, self-avoidance ensures that a neuron’s processes arborize to evenly fill a particular spatial domain. At the individual cell level, self-avoidance is promoted by genes encoding cell-surface molecules capable of generating thousands of diverse isoforms, such as Dscam1 (Down syndrome cell adhesion molecule 1) in Drosophila. Isoform choice differs between neighboring cells, allowing neurons to distinguish “self” from “nonself”. In the mouse retina, Dscam promotes self-avoidance at the level of cell types, but without extreme isoform diversity. Therefore, we hypothesize that DSCAM is a general self-avoidance cue that “masks” other cell type-specific adhesion systems to prevent overly exuberant adhesion. Here, we provide in vivo and in vitro evidence that DSCAM masks the functions of members of the cadherin superfamily, supporting this hypothesis. Thus, unlike the isoform-rich molecules tasked with self-avoidance at the individual cell level, here the diversity resides on the adhesive side, positioning DSCAM as a generalized modulator of cell adhesion during neural development.

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Section: Discussionmentioning

confidence: 99%

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members

Garrett

Khalil

Walton

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…They mediate a variety of processes, including neuronal survival, morphogenesis and connectivity, synaptic maintenance, and spatial patterning of axons and dendrites [86]. The variants in PCDH genes have been reported to be associated with dyslexia and bipolar disorder [87, 88].…”

Section: Discussionmentioning

confidence: 99%

Influence of genetic factors on long-term treatment related neurocognitive complications, and on anxiety and depression in survivors of childhood acute lymphoblastic leukemia: The Petale study

et al. 2019

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Background A substantial number of survivors of childhood acute lymphoblastic leukemia suffer from treatment-related late adverse effects including neurocognitive impairment. While multiple studies have described neurocognitive outcomes in childhood acute lymphoblastic leukemia (ALL) survivors, relatively few have investigated their association with individual genetic constitution. Methods To further address this issue, genetic variants located in 99 genes relevant to the effects of anticancer drugs and in 360 genes implicated in nervous system function and predicted to affect protein function, were pooled from whole exome sequencing data of childhood ALL survivors (PETALE cohort) and analyzed for an association with neurocognitive complications, as well as with anxiety and depression. Variants that sustained correction for multiple testing were genotyped in entire cohort (n = 236) and analyzed with same outcomes. Results Common variants in MTR , PPARA , ABCC3 , CALML5 , CACNB2 and PCDHB10 genes were associated with deficits in neurocognitive tests performance, whereas a variant in SLCO1B1 and EPHA5 genes was associated with anxiety and depression. Majority of associations were modulated by intensity of treatment. Associated variants were further analyzed in an independent SJLIFE cohort of 545 ALL survivors. Two variants, rs1805087 in methionine synthase, MTR and rs58225473 in voltage-dependent calcium channel protein encoding gene, CACNB2 are of particular interest, since associations of borderline significance were found in replication cohort and remain significant in combined discovery and replication groups (OR = 1.5, 95% CI, 1–2.3; p = 0.04 and; OR = 3.7, 95% CI, 1.25–11; p = 0.01, respectively). Variant rs4149056 in SLCO1B1 gene also deserves further attention since previously shown to affect methotrexate clearance and short-term toxicity in ALL patients. Conclusions Current findings can help understanding of the influence of genetic component on long-term neurocognitive impairment. Further studies are needed to confirm whether identified variants may be useful in identifying survivors at increased risk of these complications.

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“…All identified variants clustered in the variable 5′ exons, which encode for the extracellular protocadherin domain. Protocadherins are predominantly expressed in the developing human brain and are known to play a role in neuronal connectivity, thus ensuring formation and maintenance of neural circuits [ 70 ].…”

Section: Exploring Genetic Susceptibility To Sld—the Early Timesmentioning

confidence: 99%

The Polygenic Nature and Complex Genetic Architecture of Specific Learning Disorder

et al. 2021

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Specific Learning Disorder (SLD) is a multifactorial, neurodevelopmental disorder which may involve persistent difficulties in reading (dyslexia), written expression and/or mathematics. Dyslexia is characterized by difficulties with speed and accuracy of word reading, deficient decoding abilities, and poor spelling. Several studies from different, but complementary, scientific disciplines have investigated possible causal/risk factors for SLD. Biological, neurological, hereditary, cognitive, linguistic-phonological, developmental and environmental factors have been incriminated. Despite worldwide agreement that SLD is highly heritable, its exact biological basis remains elusive. We herein present: (a) an update of studies that have shaped our current knowledge on the disorder’s genetic architecture; (b) a discussion on whether this genetic architecture is ‘unique’ to SLD or, alternatively, whether there is an underlying common genetic background with other neurodevelopmental disorders; and, (c) a brief discussion on whether we are at a position of generating meaningful correlations between genetic findings and anatomical data from neuroimaging studies or specific molecular/cellular pathways. We conclude with open research questions that could drive future research directions.

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Ancestral Variations of the PCDHG Gene Cluster Predispose to Dyslexia in a Multiplex Family

Cited by 12 publications

References 66 publications

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members

Influence of genetic factors on long-term treatment related neurocognitive complications, and on anxiety and depression in survivors of childhood acute lymphoblastic leukemia: The Petale study

The Polygenic Nature and Complex Genetic Architecture of Specific Learning Disorder

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