A splice site mutation in <i>HERC1</i> leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum

Aggarwal, Shagun; Bhowmik, Aneek Das; Ramprasad, Vedam Lakshmi; Murugan, Sakthivel; Dalal, Ashwin

doi:10.1002/ajmg.a.37654

Cited by 33 publications

(30 citation statements)

References 10 publications

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“…Biallelic Herc1 mutation causes in humans a polymorphic syndrome with varied signs and symptoms 6 – 8 , together with intellectual disability [see table 1 in ref. 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…All counting was done with the Fiji ImageJ software (W. Rasband, National Institutes of Health, https ://image j-nih.gov/ij/). Parameters considered here were: (1) the total number of vesicles; (2) the active zone length; (3) the synaptic vesicles diameter; (4) the intervesicular distance; (5) the number of docked vesicles; (6) the number of tethered vesicles; (7) the number of synaptic vesicles for each 75 nm width compartments; (8) the number of CLT coated vesicles; (9) the number of endocytic pits; (10) the number of endosomes; and (11) the maximum diameter of the endosomes.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, mutations in the RCC1 domain of human HERC1 have been related with X-linked retinitis pigmentosa and juvenile amyotrophic lateral sclerosis 2 5 . In humans, missense mutations of Herc1 display polymorphic syndromes with or without cerebellar affectation 6 – 8 , in which the intellectual disability appears as the common neurological disorder 8 .…”

Section: Introductionmentioning

confidence: 99%

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The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

Montes-Fernández

Pérez-Villegas

Garcia-Gonzalo

et al. 2020

Sci Rep

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HERC1 is a ubiquitin ligase protein, which, when mutated, induces several malformations and intellectual disability in humans. The animal model of HERC1 mutation is the mouse tambaleante characterized by: (1) overproduction of the protein; (2) cerebellar Purkinje cells death by autophagy; (3) dysregulation of autophagy in spinal cord motor neurons, and CA3 and neocortical pyramidal neurons; (4) impairment of associative learning, linked to altered spinogenesis and absence of LTP in the lateral amygdala; and, (5) motor impairment due to delayed action potential transmission, decrease synaptic transmission efficiency and altered myelination in the peripheral nervous system. To investigate the putative role of HERC1 in the presynaptic dynamics we have performed a series of experiments in cultured tambaleante hippocampal neurons by using transmission electron microscopy, FM1-43 destaining and immunocytochemistry. Our results show: (1) a decrease in the number of synaptic vesicles; (2) reduced active zones; (3) less clathrin immunoreactivity and less presynaptic endings over the hippocampal main dendritic trees; which contrast with (4) a greater number of endosomes and autophagosomes in the presynaptic endings of the tambaleante neurons relative to control ones. Altogether these results show an important role of HERC1 in the regulation of presynaptic membrane dynamics. HERC1 is a giant phylogenetically conserved ubiquitin ligase of the HECT family 1 that participates in the ubiquitin-proteasome system (UPS) 2-3. Like other UPS alterations, mutations in HECT E3 ligases have been associated with the pathogenesis of neuromuscular disorders, Parkinson's disease and diseases of the autism spectrum 1-4. Furthermore, mutations in the RCC1 domain of human HERC1 have been related with X-linked retinitis pigmentosa and juvenile amyotrophic lateral sclerosis 2 5. In humans, missense mutations of Herc1 display polymorphic syndromes with or without cerebellar affectation 6-8 , in which the intellectual disability appears as the common neurological disorder 8. The tambaleante (tbl) mutant mouse was earliest reported as a model of adult cerebellar ataxia caused by the almost complete autophagy cell death of cerebellar Purkinje cells 9-11. In addition to adult cerebellar Purkinje cell degeneration 5,9-12 , other alterations in the central and the peripheral nervous system have been recently described in tbl mouse such as: (1) increase of autophagy signs in spinal cord motor neurons and neocortical and CA3 hippocampal pyramidal neurons 13 ; (2) impairment of the associative learning associated to absence of long term potentiation (LTP), altered dendritic spinogenesis, and a drastic decrease of glutamatergic innervation of the lateral amygdala 14 ; (3) anomalous myelination in the sciatic nerve together with alterations of non-myelinating terminal Schwann cells at the neuromuscular junction (NMJ) 15 ; and, (4) altered motor performance owing to a reduction of the motor end-plate area, and impaired evoked neurotransmitter release at the...

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“…Biallelic Herc1 mutation causes in humans a polymorphic syndrome with varied signs and symptoms 6 – 8 , together with intellectual disability [see table 1 in ref. 8 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

Montes-Fernández

Pérez-Villegas

Garcia-Gonzalo

et al. 2020

Sci Rep

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“…Mutations in another GTPase activator, HERC1, which is localized to the cytoplasm and GA/vesicular compartments and acts as a GEF for ARF1, and possibly RAB3A and RAB5 [123], also result in a macrocephaly syndrome with dysmorphic facies and psychomotor retardation (MDFPMR; MIM #617011) [124][125][126].…”

Section: Imentioning

confidence: 99%

Golgipathies in Neurodevelopment: A New View of Old Defects

et al. 2018

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“…Seizures were present in 2 patients. MRI may be normal or may demonstrate a thick corpus callosum, cerebellar hypoplasia, or ventriculomegaly [Ortega-Recalde et al, 2015;Aggarwal et al, 2016;Nguyen et al, 2016].…”

Section: Macrocephaly Dysmorphic Facies and Psychomotor Retardationmentioning

confidence: 99%

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

et al. 2018

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The overgrowth syndromes are important to diagnose, not just for accurate genetic counseling, but also for knowledge surrounding cancer surveillance and prognosis. There has been a recent expansion in the number of genes associated with a mendelian overgrowth phenotype, so this review updates previous classifications of overgrowth syndromes. We also describe a clinical and molecular approach to the investigation of individuals presenting with overgrowth. This review aims to assist the clinical diagnosis of generalized overgrowth syndromes by outlining the salient features of well-known overgrowth syndromes alongside the many syndromes that have been discovered and classified more recently. We provide key clinical “handles” to aid clinical diagnosis and a list of genes to aid with panel design when using next generation sequencing, which we believe is frequently needed due to the overlapping phenotypic features seen between overgrowth syndromes.

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A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum

Cited by 33 publications

References 10 publications

The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

Golgipathies in Neurodevelopment: A New View of Old Defects

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

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