Cinthia Aguilera - Academia.edu (original) (raw)

Uploads

Papers by Cinthia Aguilera

Research paper thumbnail of The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome

Frontiers in Neuroscience

KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of syna... more KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of synaptic vesicle precursors in neurons. Pathogenic variants in KIF1A have been associated with a wide spectrum of neurological disorders. Here, we report a patient presenting a severe neurodevelopmental disorder carrying a novel de novo missense variant p.Arg169Thr (R169T) in the KIF1A motor domain. The clinical features present in our patient match with those reported for NESCAV syndrome including severe developmental delay, spastic paraparesis, motor sensory neuropathy, bilateral optic nerve atrophy, progressive cerebellar atrophy, epilepsy, ataxia, and hypotonia. Here, we demonstrate that the microtubule-stimulated ATPase activity of the KIF1A is strongly reduced in the motor domain of the R169T variant. Supporting this, in silico structural modeling suggests that this variant impairs the interaction of the KIF1A motor domain with microtubules. The characterization of the molecular effect...

Research paper thumbnail of New genes involved in Angelman syndrome-like: expanding the genetic spectrum

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay wit... more Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis. New AS-like genes do not interact directly with UBE3A gene product but are involved in synapsis and neuron system development.

Research paper thumbnail of Identification of a de novo splicing variant in the Coffin–Siris gene, SMARCE 1, in a patient with Angelman‐like syndrome

Molecular Genetics & Genomic Medicine, 2018

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual disa... more Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual disability, lack of speech, ataxia of gait, seizures, a characteristic electroencephalography (EEG), and a unique behavior that includes any combination of happy demeanor, easily excitable personality, frequent laughter, and stereotypes (Bird, 2014; Buiting, 2010). AS is caused by the lack of expression of the maternally inherited UBE3A gene (OMIM 601623) in neurons. Around 10% of patients with a clinical diagnosis of AS are not molecularly confirmed (Dagli,

Research paper thumbnail of Novel intragenic deletions within the UBE3A gene in two unrelated patients with Angelman syndrome: case report and review of the literature

BMC medical genetics, Nov 21, 2017

Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence ... more Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence of speech, distinctive dysmorphic craniofacial features, ataxia and a characteristic behavioral phenotype. AS is caused by the lack of expression in neurons of the UBE3A gene, which is located in the 15q11.2-q13 imprinted region. Functional loss of UBE3A is due to 15q11.2-q13 deletion, mutations in the UBE3A gene, paternal uniparental disomy and genomic imprinting defects. We report here two patients with clinical features of AS referred to our hospital for clinical follow-up and genetic diagnosis. Methylation Specific-Multiplex Ligation-Dependent Probe Amplification (MS-MLPA) of the 15q11.2-q13 region was carried out in our laboratory as the first diagnostic tool detecting two novel UBE3A intragenic deletions. Subsequently, the MLPA P336-A2 kit was used to confirm and determine the size of the UBE3A deletion in the two patients. A review of the clinical features of previously reported p...

Research paper thumbnail of The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome

Frontiers in Neuroscience

KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of syna... more KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of synaptic vesicle precursors in neurons. Pathogenic variants in KIF1A have been associated with a wide spectrum of neurological disorders. Here, we report a patient presenting a severe neurodevelopmental disorder carrying a novel de novo missense variant p.Arg169Thr (R169T) in the KIF1A motor domain. The clinical features present in our patient match with those reported for NESCAV syndrome including severe developmental delay, spastic paraparesis, motor sensory neuropathy, bilateral optic nerve atrophy, progressive cerebellar atrophy, epilepsy, ataxia, and hypotonia. Here, we demonstrate that the microtubule-stimulated ATPase activity of the KIF1A is strongly reduced in the motor domain of the R169T variant. Supporting this, in silico structural modeling suggests that this variant impairs the interaction of the KIF1A motor domain with microtubules. The characterization of the molecular effect...

Research paper thumbnail of New genes involved in Angelman syndrome-like: expanding the genetic spectrum

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay wit... more Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis. New AS-like genes do not interact directly with UBE3A gene product but are involved in synapsis and neuron system development.

Research paper thumbnail of Identification of a de novo splicing variant in the Coffin–Siris gene, SMARCE 1, in a patient with Angelman‐like syndrome

Molecular Genetics & Genomic Medicine, 2018

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual disa... more Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual disability, lack of speech, ataxia of gait, seizures, a characteristic electroencephalography (EEG), and a unique behavior that includes any combination of happy demeanor, easily excitable personality, frequent laughter, and stereotypes (Bird, 2014; Buiting, 2010). AS is caused by the lack of expression of the maternally inherited UBE3A gene (OMIM 601623) in neurons. Around 10% of patients with a clinical diagnosis of AS are not molecularly confirmed (Dagli,

Research paper thumbnail of Novel intragenic deletions within the UBE3A gene in two unrelated patients with Angelman syndrome: case report and review of the literature

BMC medical genetics, Nov 21, 2017

Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence ... more Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence of speech, distinctive dysmorphic craniofacial features, ataxia and a characteristic behavioral phenotype. AS is caused by the lack of expression in neurons of the UBE3A gene, which is located in the 15q11.2-q13 imprinted region. Functional loss of UBE3A is due to 15q11.2-q13 deletion, mutations in the UBE3A gene, paternal uniparental disomy and genomic imprinting defects. We report here two patients with clinical features of AS referred to our hospital for clinical follow-up and genetic diagnosis. Methylation Specific-Multiplex Ligation-Dependent Probe Amplification (MS-MLPA) of the 15q11.2-q13 region was carried out in our laboratory as the first diagnostic tool detecting two novel UBE3A intragenic deletions. Subsequently, the MLPA P336-A2 kit was used to confirm and determine the size of the UBE3A deletion in the two patients. A review of the clinical features of previously reported p...