PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention

Johnson, Emily M.; Ishak, Alexandra; Naylor, Paige E.; Stevenson, David A.; Reiss, Allan L.; Green, Tamar

doi:10.1093/cercor/bhy158

Cited by 24 publications

(45 citation statements)

References 51 publications

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“…In addition to their recognized NDDs, infants and children with CHD are at high risk for abnormal MRI studies of the brain, and recent data suggest a correlation of behavior with alterations in the connectome. To better explore these findings, prior studies have addressed either the impact of targeted CHD variants on brain development and neurodevelopmental outcome 93 , or identified genes that are both highly expressed in the developing heart and contribute to NDD or brain development. However, none have provided analyses of large cohorts with MRI measures of neural connectivity.…”

Section: Genementioning

confidence: 99%

De novo damaging variants associated with congenital heart diseases contribute to the connectome

Ji¹,

Ferdman²,

Copel³

et al. 2020

Sci Rep

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congenital heart disease (cHD) survivors are at risk for neurodevelopmental disability (nDD), and recent studies identify genes associated with both disorders, suggesting that nDD in cHD survivors may be of genetic origin. Genes contributing to neurogenesis, dendritic development and synaptogenesis organize neural elements into networks known as the connectome. We hypothesized that nDD in cHD may be attributable to genes altering both neural connectivity and cardiac patterning. to assess the contribution of de novo variants (DNVs) in connectome genes, we annotated 229 published NDD genes for connectome status and analyzed data from 3,684 CHD subjects and 1,789 controls for connectome gene mutations. cHD cases had more protein truncating and deleterious missense DnVs among connectome genes compared to controls (oR = 5.08, 95%CI:2.81-9.20, Fisher's exact test P = 6.30E-11). When removing three known syndromic CHD genes, the findings remained significant (OR = 3.69, 95%CI:2.02-6.73, Fisher's exact test P = 1.06E-06). In CHD subjects, the top 12 NDD genes with damaging DNVs that met statistical significance after Bonferroni correction (PTPN11,

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Section: Genementioning

confidence: 99%

De novo damaging variants associated with congenital heart diseases contribute to the connectome

Ji¹,

Ferdman²,

Copel³

et al. 2020

Sci Rep

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“…Among the organ systems most commonly impacted in all RASopathies is the central nervous system. Disruption to molecular, cellular, and neural systems as a result of gene mutations in the RAS‐MAPK pathway can lead to a multitude of neurobiological differences, including neuroanatomical abnormalities, aberrant white matter microstructure, impaired synaptic plasticity, and altered neurotransmitter function (Johnson et al, ; Loitfelder et al, ; Mainberger, Langer, Mall, & Jung, ; Shilyansky et al, ). While most individuals with NF1 or NS have intact intellectual function, there is increased vulnerability to a variety of well‐documented neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and learning disabilities (Eijk et al, ; Lehtonen, Howie, Trump, & Huson, ; Pierpont, ).…”

Section: Introductionmentioning

confidence: 99%

Emotional functioning among children with neurofibromatosis type 1 or Noonan syndrome

McNeill

Hudock

Foy

et al. 2019

American J of Med Genetics Pt A

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While neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are clinically distinct genetic syndromes, they have overlapping features because they are caused by pathogenic variants in genes encoding molecules within the Ras-mitogen-activated protein kinase signaling pathway. Increased risk for emotional and behavioral challenges has been reported in both children and adults with these syndromes. The current study examined parent-report and self-report measures of emotional functioning among children with NF1 and NS as compared to their unaffected siblings. Parents and children with NS (n = 39), NF1 (n = 39), and their siblings without a genetic condition (n = 32) completed well-validated clinical symptom rating scales. Results from parent questionnaires indicated greater symptomatology on scales measuring internalizing behaviors and symptoms of attention deficit hyperactivity disorder (ADHD) in both syndrome groups as compared with unaffected children. Frequency and severity of emotional and behavioral symptoms were remarkably similar across the two clinical groups. Symptoms of depression and anxiety were higher in children who were also rated as meeting symptom criteria for ADHD. While self-report ratings by children generally correlated with parent ratings, symptom severity was less pronounced. Among unaffected siblings, parent ratings indicated higher than expected levels of anxiety. Study findings may assist with guiding family-based interventions to address emotional challenges. K E Y W O R D Sanxiety, depression, emotional function, neurofibromatosis type 1, Noonan syndrome, RASopathies

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“…In addition to intellectual disability, ADHD is frequently diagnosed in Noonan Syndrome and NF1, two common RASopathies (Johnson et al, 2019; Miguel et al, 2015; Pierpont et al, 2015). Abnormal PFC function has been linked to ADHD (Seidman et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Hyperactive MEK1 signaling in cortical GABAergic neurons causes embryonic parvalbumin-neuron death and defects in behavioral inhibition

Holter

Hewitt

Nishimura

et al. 2019

Preprint

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1Abnormal ERK/MAPK pathway activity is an important contributor to the neuropathogenesis of 2 many disorders including Fragile X, Rett, 16p11.2 Syndromes, and the RASopathies. Individuals with these 3 syndromes often present with intellectual disability, ADHD, autism, and epilepsy. However, the 4 pathological mechanisms that underly these deficits are not fully understood. Here, we examined whether 5 hyperactivation of MEK1 signaling modifies the development of GABAergic cortical interneurons (CINs), 6 a heterogeneous population of inhibitory neurons necessary for cortical function. We show that 7 GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling 8 in a subpopulation of immature neurons in the embryonic subpallium. Adult mutants displayed a significant 9 loss of mature parvalbumin-expressing (PV) CINs, but not somatostatin-expressing CINs, during postnatal 10 development and a modest reduction in perisomatic inhibitory synapse formation on excitatory neurons. 11Surviving mutant PV-CINs maintained a typical fast-spiking phenotype and minor differences in intrinsic 12 electrophysiological properties. These changes coincided with an increased risk of seizure-like phenotypes. 13 In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of 14 perineuronal nets, an extracellular structure thought to restrict plasticity in the developing brain. Indeed, we 15 found that mutants exhibit a significant impairment in the acquisition of a behavioral test that relies on 16 behavioral response inhibition, a process linked to ADHD-like phenotypes. Overall, our data suggests PV-17

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PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention

Cited by 24 publications

References 51 publications

De novo damaging variants associated with congenital heart diseases contribute to the connectome

De novo damaging variants associated with congenital heart diseases contribute to the connectome

Emotional functioning among children with neurofibromatosis type 1 or Noonan syndrome

Hyperactive MEK1 signaling in cortical GABAergic neurons causes embryonic parvalbumin-neuron death and defects in behavioral inhibition

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