Novel CLTC variants cause new brain and kidney phenotypes

Itai, Toshiyuki; Miyatake, Satoko; Tsuchida, Naomi; Saida, Ken; Narahara, Sho; Tsuyusaki, Yu; Castro, Matheus Augusto Araújo; Kim, Chong; Okamoto, Nobuhiko; Uchiyama, Yuri; Koshimizu, Eriko; Hamanaka, Kohei; Fujita, Atsushi; Mizuguchi, Takeshi; Matsumoto, Naomichi

doi:10.1038/s10038-021-00957-3

Cited by 4 publications

(11 citation statements)

References 19 publications

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“…De novo CLTC missense, truncating, and deletion variants cause human disease (DeMari et al, 2016; Itai et al, 2022; Manti et al, 2019; Murdock et al, 2021; Nabais Sa et al, 2020) (Table 1). More severe disease occurs with missense and in‐frame alterations than with truncating variants suggesting that missense and in‐frame alterations act by a gain‐of‐function mechanism, whereas the truncating variants act by a loss‐of‐function mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Generation of tandem alternative splice acceptor sites and CLTC haploinsufficiency: A cause of CLTC‐related disorder

Sage,

Lee,

Dalmann

et al. 2023

American J of Med Genetics Pt A

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Tandem splice acceptors (NAGN n AG) are a common mechanism of alternative splicing, but variants that are likely to generate or to disrupt tandem splice sites have rarely been reported as disease causing. We identify a pathogenic intron ];[=]) in a propositus with intellectual disability and behavioral problems. By RNAseq analysis of peripheral blood mRNA, this variant generates transcripts using cryptic proximal splice acceptors (NM_004859.4: r.3765_3766insTTCACAGAAAGGAACTAG, and NM_004859.4: r.3765_3766insAAAGGAACTAG). Given that the propositus expresses 38% the level of CLTC transcripts as unaffected controls, these variant transcripts, which encode premature termination codons, likely undergo nonsense mediated mRNA decay (NMD). This is the first functional evidence for CLTC haploinsufficiency as a cause of CLTC-related disorder and the first evidence that the generation of tandem alternative splice sites causes CLTC-related disorder. We suggest that variants creating tandem alternative splice sites are an underreported disease mechanism and that transcriptome-level analysis should be routinely pursued to define the pathogenicity of such variants.

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Section: Discussionmentioning

confidence: 99%

“…De novo CLTC missense, truncating, and deletion variants cause human disease (DeMari et al, 2016;Itai et al, 2022;Manti et al, 2019;Murdock et al, 2021;Nabais Sa et al, 2020) (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Generation of tandem alternative splice acceptor sites and CLTC haploinsufficiency: A cause of CLTC‐related disorder

Sage,

Lee,

Dalmann

et al. 2023

American J of Med Genetics Pt A

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“…De novo mutations in CLTC underlie a wide spectrum of infantile and childhood neurodevelopmental phenotypes, including developmental and epileptic encephalopathy (DEE), movement disorders (MD), and intellectual disability (ID) ( DeMari et al, 2016 ; Lelieveld et al, 2016 ; Hamdan et al, 2017 ; Nabais Sá et al, 2020 ; Fernández-Mayoralas et al, 2021 ; Itai et al, 2022 ). The phenotypic spectrum is highly variable and ranges from mild ID with or without behavioral issues, particularly autistic features and attention deficit hyperactivity disorder (ADHD), to severe ID and refractory epilepsy.…”

Section: Introductionmentioning

confidence: 99%

The recurrent pathogenic Pro890Leu substitution in CLTC causes a generalized defect in synaptic transmission in Caenorhabditis elegans

Pannone

Muto

Nardecchia

et al. 2023

Front. Mol. Neurosci.

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De novo CLTC mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders (MD) as major clinical features. CLTC encodes the widely expressed heavy polypeptide of clathrin, a major component of the coated vesicles mediating endocytosis, intracellular trafficking, and synaptic vesicle recycling. The underlying pathogenic mechanism is largely unknown. Here, we assessed the functional impact of the recurrent c.2669C > T (p.P890L) substitution, which is associated with a relatively mild ID/MD phenotype. Primary fibroblasts endogenously expressing the mutated protein show reduced transferrin uptake compared to fibroblast lines obtained from three unrelated healthy donors, suggesting defective clathrin-mediated endocytosis. In vitro studies also reveal a block in cell cycle transition from G0/G1 to the S phase in patient’s cells compared to control cells. To demonstrate the causative role of the p.P890L substitution, the pathogenic missense change was introduced at the orthologous position of the Caenorhabditis elegans gene, chc-1 (p.P892L), via CRISPR/Cas9. The resulting homozygous gene-edited strain displays resistance to aldicarb and hypersensitivity to PTZ, indicating defective release of acetylcholine and GABA by ventral cord motor neurons. Consistently, mutant animals show synaptic vesicle depletion at the sublateral nerve cords, and slightly defective dopamine signaling, highlighting a generalized deficit in synaptic transmission. This defective release of neurotransmitters is associated with their secondary accumulation at the presynaptic membrane. Automated analysis of C. elegans locomotion indicates that chc-1 mutants move slower than their isogenic controls and display defective synaptic plasticity. Phenotypic profiling of chc-1 (+/P892L) heterozygous animals and transgenic overexpression experiments document a mild dominant-negative behavior for the mutant allele. Finally, a more severe phenotype resembling that of chc-1 null mutants is observed in animals harboring the c.3146 T > C substitution (p.L1049P), homologs of the pathogenic c.3140 T > C (p.L1047P) change associated with a severe epileptic phenotype. Overall, our findings provide novel insights into disease mechanisms and genotype–phenotype correlations of CLTC-related disorders.

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“…2 CLTC is highly expressed in the developing brain and de novo mutations in this gene underlie a wide spectrum of infantile and childhood neurodevelopmental disorders, including facial dysmorphism, brain malformations, musculoskeletal defects, intellectual disability, and epileptic encephalopathy (MIM 617854). [3][4][5][6][7][8] Although CLTC deficiency may affect the neurotransmitters vesicle recycle, 6 the precise underlying pathogenic mechanisms remain largely unknown. Here, we report on the positive effect of monoamine oxidase B (MAO-B) inhibitor selegiline on the movement disorder (MD) of a CLTC-positive subject.…”

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confidence: 99%

“…MD spectrum is heterogeneous in CLTC defect and is summarized in Table S1. [3][4][5][6][7] Severe cases are associated with in-frame or missense variants that induce a dominant-negative effect, whereas nonsense and frameshift variants, resulting in haploinsufficiency, would be associated with a milder phenotype. 6 CLTC deficiency should be suspected in individuals with neurodevelopmental disorders, possibly associated with facial dysmorphisms, early-onset hyperkinetic MD or parkinsonism, spastic-ataxic cerebral palsy-like phenotype, and brain abnormalities (such as thin corpus callosum or cerebellar atrophy/hypoplasia).…”

mentioning

confidence: 99%

Improvement of Movement Disorder and Neurodevelopment under Selegiline in a CLTC‐Deficient Patient

Nardecchia

Bove

Pollini

et al. 2023

Movement Disord Clin Pract

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Novel CLTC variants cause new brain and kidney phenotypes

Cited by 4 publications

References 19 publications

Generation of tandem alternative splice acceptor sites and CLTC haploinsufficiency: A cause of CLTC‐related disorder

Generation of tandem alternative splice acceptor sites and CLTC haploinsufficiency: A cause of CLTC‐related disorder

The recurrent pathogenic Pro890Leu substitution in CLTC causes a generalized defect in synaptic transmission in Caenorhabditis elegans

Improvement of Movement Disorder and Neurodevelopment under Selegiline in a CLTC‐Deficient Patient

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