XLMR protein related to neurite extension (Xpn/KIAA2022) regulates cell–cell and cell–matrix adhesion and migration

Magome, Takuya; Hattori, Tsuyoshi; Taniguchi, Manabu; Ishikawa, Tomoyoshi; Miyata, Sumiko; Yamada, Kohei; Takamura, Hironori; Matsuzaki, Shinsuke; Ito, Akira; Tohyama, Masaya; Katayama, Taiichi

doi:10.1016/j.neuint.2013.09.011

Cited by 25 publications

(22 citation statements)

References 44 publications

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“…A previous study indicated that in PC12 cells, knockdown of KIDLIA upregulates the expression of N-cadherin (Magome et al, 2013). We therefore sought to investigate whether knockdown of KIDLIA affected N-cadherin expression and localization in neurons.…”

Section: Resultsmentioning

confidence: 99%

The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling

Gilbert

Man

2016

eNeuro

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Our previous work showed that loss of the KIAA2022 gene protein results in intellectual disability with language impairment and autistic behavior (KIDLIA, also referred to as XPN). However, the cellular and molecular alterations resulting from a loss of function of KIDLIA and its role in autism with severe intellectual disability remain unknown. Here, we show that KIDLIA plays a key role in neuron migration and morphogenesis. We found that KIDLIA is distributed exclusively in the nucleus. In the developing rat brain, it is expressed only in the cortical plate and subplate region but not in the intermediate or ventricular zone. Using in utero electroporation, we found that short hairpin RNA (shRNA)-mediated knockdown of KIDLIA leads to altered neuron migration and a reduction in dendritic growth and disorganized apical dendrite projections in layer II/III mouse cortical neurons. Consistent with this, in cultured rat neurons, a loss of KIDLIA expression also leads to suppression of dendritic growth and branching. At the molecular level, we found that KIDLIA suppression leads to an increase in cell-surface N-cadherin and an elevated association of N-cadherin with δ-catenin, resulting in depletion of free δ-catenin in the cytosolic compartment. The reduced availability of cytosolic δ-catenin leads to elevated RhoA activity and reduced actin dynamics at the dendritic growth cone. Furthermore, in neurons with KIDLIA knockdown, overexpression of δ-catenin or inhibition of RhoA rescues actin dynamics, dendritic growth, and branching. These findings provide the first evidence on the role of the novel protein KIDLIA in neurodevelopment and autism with severe intellectual disability.

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Section: Resultsmentioning

confidence: 99%

The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling

Gilbert

Man

2016

eNeuro

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“…Brain mosaicism in females, as a result of random X-inactivation, was proposed to disrupt cell–cell interactions between the two different cell populations (the cells with normal PCDH19 on the one hand, and the cells with mutated PCDH19 on the other). A similar disease mechanism is plausible, since the KIAA2022 protein seems to be involved in the same processes of cell–cell and cell–matrix adhesion and neuronal migration as the PCHD19 protein, by influencing expression of N-cadherin 7. Additional X-inactivation and expression studies of asymptomatic mothers of affected males carrying KIAA2022 mutations could further clarify the disease mechanism in females with KIAA2022- related disease.…”

Section: Discussionmentioning

confidence: 95%

De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

et al. 2016

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BackgroundMutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual disability and epilepsy.MethodsReported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible.ResultsAll mutations were predicted to result in a frameshift or premature stop. 12 out of 14 patients had intractable epilepsy with myoclonic and/or absence seizures, and generalised in 11. Thirteen patients had mild to severe intellectual disability. This female phenotype partially overlaps with the reported male phenotype which consists of more severe intellectual disability, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation, complete absence of RNA expression in blood and a phenotype similar to male patients. In the six other tested patients, X-inactivation was random, confirmed by a non-significant twofold to threefold decrease of RNA expression in blood, consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles.ConclusionsHeterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.

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“…KIAA2022 mutation is suspected to be associated with hypothalamic dysfunction, leading to central hypothyroidism in Patient 2. Xpn (mouse ortholog of KIAA2022 ) knockdown enhanced cell–cell and cell–matrix adhesion mediated by N‐cadherin and beta 1 integrin [Magome et al, ]. The beta 1 integrin showed characteristic expression pattern during nephrogenesis and is crucial for normal development and function of the renal glomeruli [Kanasaki et al, ].…”

Section: Discussionmentioning

confidence: 99%

Delineation of the KIAA2022 mutation phenotype: Two patients with X‐linked intellectual disability and distinctive features

Kuroda

Ohashi

Naruto

et al. 2015

American J of Med Genetics Pt A

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Next-generation sequencing has enabled the screening for a causative mutation in X-linked intellectual disability (XLID). We identified KIAA2022 mutations in two unrelated male patients by targeted sequencing. We selected 13 Japanese male patients with severe intellectual disability (ID), including four sibling patients and nine sporadic patients. Two of thirteen had a KIAA2022 mutation. Patient 1 was a 3-year-old boy. He had severe ID with autistic behavior and hypotonia. Patient 2 was a 5-year-old boy. He also had severe ID with autistic behavior, hypotonia, central hypothyroidism, and steroid-dependent nephrotic syndrome. Both patients revealed consistent distinctive features, including upswept hair, narrow forehead, downslanting eyebrows, wide palpebral fissures, long nose, hypoplastic alae nasi, open mouth, and large ears. De novo KIAA2022 mutations (p.Q705X in Patient 1, p.R322X in Patient 2) were detected by targeted sequencing and confirmed by Sanger sequencing. KIAA2022 mutations and alterations have been reported in only four families with nonsyndromic ID and epilepsy. KIAA2022 is highly expressed in the fetal and adult brain and plays a crucial role in neuronal development. These additional patients support the evidence that KIAA2022 is a causative gene for XLID.

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XLMR protein related to neurite extension (Xpn/KIAA2022) regulates cell–cell and cell–matrix adhesion and migration

Cited by 25 publications

References 44 publications

The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling

The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling

De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

Delineation of the KIAA2022 mutation phenotype: Two patients with X‐linked intellectual disability and distinctive features

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