Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the ...phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features.
Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay.
We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance.
In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.
The recent advances in high throughput sequencing technology have drastically changed the practice of medical diagnosis, allowing for rapid identification of hundreds of genes causing human diseases. ...This unprecedented progress has made clear that most forms of intellectual disability that affect more than 3% of individuals worldwide are monogenic diseases. Strikingly, a substantial fraction of the dominant forms of intellectual disability is associated with genes related to the ubiquitin-proteasome system, a highly conserved pathway made up of approximately 1200 genes involved in the regulation of protein homeostasis. This group is currently emerging a new class of neurodevelopmental disorders specifically caused by proteasome pathogenic variants which we propose to designate “neurodevelopmental proteasomopathies”. Besides cognitive impairment, these diseases are typically associated with a series of syndromic clinical manifestations, among which facial dysmorphism, motor delay, and failure to thrive are the most prominent ones. While recent efforts have been made to uncover the effects exerted by proteasome variants on cell and tissue landscapes, the molecular pathogenesis of neurodevelopmental proteasomopathies remains ill-defined. In this review, we discuss the cellular changes typically induced by genomic alterations in proteasome genes and explore their relevance as biomarkers for the diagnosis, management, and potential treatment of these new rare disease entities.
Highlights • Aim: toxicological evaluation of Mira-1, first described as a mutant P53-reactivating agent. • Acute cytotoxicity of Mira-1 against human normal epithelial and primary mesenchymal cells. ...• Mira-1 cytotoxicity is restricted to actively proliferating cells. • Acute cytotoxicity of Mira-1 against cancer cell lines is independent from their TP53 status. • The mira-1 cytotoxicity is mediated by a caspase-9-dependent apoptotic effect.
Le système ubiquitine-protéasome (UPS) est une voie conservée chez les eucaryotes qui permet la dégradation, par les protéasomes, des protéines modifiées par l’ubiquitine. Récemment, une corrélation ...entre des variants pathogènes de gènes codant le protéasome et l’émergence de nouvelles maladies avec troubles neurodéveloppementaux, dénommés « protéasomopathies neurodéveloppementales », a été mise en évidence. Ces maladies rares se manifestent par des retards psychomoteurs, des troubles du comportement, des dysmorphies faciales et des anomalies multi-systémiques. Dans cette synthèse, nous répertorions les biomarqueurs spécifiques d’une dysfonction protéasomale et nous discutons de leur pertinence pour le diagnostic et les traitements de ces troubles neurodéveloppementaux.
The ubiquitin-proteasome system (UPS) is a conserved degradation pathway in eukaryotes, playing a central role in various cellular processes, including maintaining protein homeostasis, regulating the cell cycle and signaling pathways, as well as orchestrating cell survival and death. Proteins targeted for UPS-mediated degradation undergo ubiquitin chain modification before being degraded by 26S proteasomes. Recently, a correlation has emerged between pathogenic proteasome variants and the onset of neurodevelopmental disorders. Termed “neurodevelopmental proteasomopathies”, these syndromes are rare and characterized by delayed psychomotor development, behavioral disorders, facial dysmorphia, and multisystemic anomalies. In this review, we examine current knowledge on proteasomal dysfunctions and assess their relevance in the search for biomarkers for the diagnosis and potential treatment of these syndromic proteasomopathies.
Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ...ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.
Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, ...a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10−21), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.
N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal ...Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.
Abstract Objective We present a case of acrodermatitis enteropathica in a full-term, breast-fed, 7-mo-old infant born from consanguineous parents with a family history of acrodermatitis ...enteropathica. Methods The patient presented with periorificial and symmetric acral lesions, which prompted us to review the clinical features of acrodermatitis enteropathica and its pathogenesis. Laboratory investigations showed low zinc levels in the infant’s and mother’s sera and in the mothers’ milk. Results A diagnosis of acrodermatitis enteropathica was made. A mutation screening of the SLC39A4 gene in the patient and his mother showed heterozygosity for the deletion c.1223_1227delCCGGG. The diagnosis of transient symptomatic zinc deficiency was then established. Conclusion Transient symptomatic zinc deficiency is generally reported in premature infants but should also be considered in full-term, breast-fed infants, as in the present case.
RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar ...Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.
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