Loss-of-Function Plays a Major Role in Early Neurogenesis of Tubulin α-1 A (TUBA1A) Mutation-Related Brain Malformations

AbstractIn light of the astronomical number of cell divisions taking place in restricted neurogenic niches, brain malformations caused by ectopic proliferation of misplaced progenitor cells are surprisingly rare. Here, we show that a process we term developmental anoikis distinguishes the abnormal detachment of progenitor cells from the normal delamination of daughter neuroblasts in the developing mouse neocortex. By using in vivo gain-of-function, loss-of-function, and rescue manipulations together with correlated confocal and super-resolution imaging, we identify the endocannabinoid-metabolizing enzyme abhydrolase domain containing 4 (ABHD4) as an essential mediator for the elimination of abnormally detached cells. Consequently, rapid ABHD4 downregulation is necessary for delaminated daughter neuroblasts to escape from anoikis. Moreover, ABHD4 is required for fetal alcohol-induced apoptosis, but not for the well-established form of developmentally controlled programmed cell death. These results suggest that ABHD4-mediated developmental anoikis specifically protects the embryonic brain from the consequences of sporadic delamination errors and teratogenic insults.

Download Full-text

Somatic mutation involving diverse genes leads to a spectrum of focal cortical malformations

10.1101/2021.12.22.21267563 ◽

2021 ◽

Author(s):

Dulcie Lai ◽

Meethila Gade ◽

Edward Yang ◽

Hyun Yong Koh ◽

Nicole M. Walley ◽

...

Keyword(s):

Focal Cortical Dysplasia ◽

Hippocampal Sclerosis ◽

Cortical Development ◽

Copy Number Variants ◽

Cortical Dysplasia ◽

Disease Genes ◽

Type I ◽

Type Ii ◽

Loss Of Function ◽

Brain Malformations

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT3-mTOR-signaling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n=16), focal cortical dysplasia type I and related phenotypes (n=48), focal cortical dysplasia type II (n=44), or focal cortical dysplasia type III (n=15) classified using imaging and pathological findings. We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel, and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1, and NIPBL, genes associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a very small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that FCD types I, II, and III, are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

Download Full-text

PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly

Science Advances ◽

10.1126/sciadv.aax9852 ◽

2020 ◽

Vol 6 (2) ◽

pp. eaax9852 ◽

Cited By ~ 1

Author(s):

Slim Mzoughi ◽

Federico Di Tullio ◽

Diana H. P. Low ◽

Corina-Mihaela Motofeanu ◽

Sheena L. M. Ong ◽

...

Keyword(s):

Candidate Genes ◽

Transcriptional Activity ◽

Embryonic Lethality ◽

Loss Of Function ◽

New Mutation ◽

Brain Malformations ◽

Pcp Signaling ◽

Genetic Deletion ◽

The Brain ◽

Anterior Posterior

Holoprosencephaly (HPE) is a congenital forebrain defect often associated with embryonic lethality and lifelong disabilities. Currently, therapeutic and diagnostic options are limited by lack of knowledge of potential disease-causing mutations. We have identified a new mutation in the PRDM15 gene (C844Y) associated with a syndromic form of HPE in multiple families. We demonstrate that C844Y is a loss-of-function mutation impairing PRDM15 transcriptional activity. Genetic deletion of murine Prdm15 causes anterior/posterior (A/P) patterning defects and recapitulates the brain malformations observed in patients. Mechanistically, PRDM15 regulates the transcription of key effectors of the NOTCH and WNT/PCP pathways to preserve early midline structures in the developing embryo. Analysis of a large cohort of patients with HPE revealed potentially damaging mutations in several regulators of both pathways. Our findings uncover an unexpected link between NOTCH and WNT/PCP signaling and A/P patterning and set the stage for the identification of new HPE candidate genes.

Download Full-text

Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

10.1101/2021.01.22.427482 ◽

2021 ◽

Author(s):

Andrea Boitnott ◽

Dévina C Ung ◽

Marta Garcia-Forn ◽

Kristi Niblo ◽

Danielle Mendonca ◽

...

Keyword(s):

Mouse Model ◽

Behavioral Problems ◽

Behavioral Changes ◽

Face Validity ◽

Motor Deficits ◽

Projection Neurons ◽

Loss Of Function ◽

Cortical Projection ◽

Glutamatergic Neurons ◽

Brain Malformations

ABSTRACTBackgroundMutations in the X-linked gene DDX3X account for ~2% of intellectual disability in females, often co-morbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis.MethodsWe generated a Ddx3x haploinsufficient mouse (Ddx3x+/−) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development.ResultsDdx3x+/− mice show physical, sensory, and motor delays that evolve into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments, and motor deficits. Motor function further declines with age. These behavioral changes are associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning is accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex.ConclusionsThese data shed new light on the developmental mechanisms driving DDX3X syndrome and support face validity of this novel pre-clinical mouse model.

Download Full-text

E3 ubiquitin ligases

Essays in Biochemistry ◽

10.1042/bse0410015 ◽

2005 ◽

Vol 41 ◽

pp. 15-30 ◽

Cited By ~ 123

Author(s):

Helen C. Ardley ◽

Philip A. Robinson

Keyword(s):

Protein Complexes ◽

Loss Of Function ◽

Direct Role ◽

Cellular Processes ◽

Substrate Protein ◽

Protein Ubiquitination ◽

C Terminus ◽

Full Complement ◽

Spatio Temporal ◽

Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

Download Full-text

Metallic prions

Biochemical Society Symposium ◽

10.1042/bss0710193 ◽

2004 ◽

Vol 71 ◽

pp. 193-202 ◽

Cited By ~ 9

Author(s):

David R Brown

Keyword(s):

Prion Protein ◽

Binding Capacity ◽

Normal Function ◽

Transmissible Spongiform Encephalopathies ◽

Published Data ◽

Normal Brain ◽

Copper Binding ◽

Loss Of Function ◽

Spongiform Encephalopathies ◽

The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

Download Full-text

Errata

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2008.marapr02 ◽

2008 ◽

Vol 13 (2) ◽

pp. 5-5

Keyword(s):

Psychotic Disorders ◽

Pain Syndrome ◽

Vestibular Disorders ◽

Loss Of Function ◽

Sixth Edition ◽

Neurologic Disorders ◽

Upper And Lower Extremities ◽

Impairment Ratings ◽

Extensive List ◽

Mental And Behavioral Disorders

Abstract Although most chapters in the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Sixth Edition, instruct evaluators to perform impairment ratings by first assigning a diagnosis-based class and then assigning a grade within that class, Chapter 13, The Central and Peripheral Nervous System, continues to use a methodology similar to that of the fifth edition. The latter was criticized for duplicating materials that were presented in other chapters and for producing different ratings, so the revision of Chapter 13 attempts to maintain consistency between this chapter and those that address mental and behavioral disorders, loss of function in upper and lower extremities, loss of bowel control, and bladder and sexual function. A table titled Summary of Chapters Used to Rate Various Neurologic Disorders directs physicians to the relevant chapters (ie, instead of Chapter 13) to consult in rating neurologic disorders; the extensive list of conditions that should be addressed in other chapters includes but is not limited to radiculopathy, plexus injuries and other plexopathies, focal neuropathy, complex regional pain syndrome, visual and vestibular disorders, and a range of primary mood, anxiety, and psychotic disorders. The article comments in detail on sections of this chapter, identifies changes in the sixth edition, and provide guidance regarding use of the new edition, resulting in less duplication and greater consistency.

Download Full-text

Impairment Tutorial: Rating Facial Disfigurement After an Injury

Guides Newsletter ◽

10.1001/amaguidesnewsletters.1998.julaug04 ◽

1998 ◽

Vol 3 (4) ◽

pp. 6-6

Author(s):

Marc T. Taylor

Keyword(s):

Current Work ◽

Workers Compensation ◽

Loss Of Function ◽

Facial Disfigurement ◽

Work Related ◽

Work Related Injury ◽

Compensation Claim ◽

Impairment Ratings

Abstract This article discusses two important cases that involve the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides). First, in Vargas v Industrial Com’n of Arizona, a claimant had a pre-existing non–work-related injury to his right knee as well as a work-related injury, and the issue was apportionment of the pre-existing injury. The court held that, under Arizona's statute, the impairment from the pre-existing injury should be subtracted from the current work-related impairment. In the second case, Colorado courts addressed the issue of apportionment in a workers’ compensation claim in which the pre-existing injury was asymptomatic at the time of the work-related injury (Askey v Industrial Claim Appeals Office). In this case, the court held that the worker's benefits should not be reduced to account for an asymptomatic pre-existing condition that could not be rated accurately using the AMA Guides. The AMA Guides bases impairment ratings on anatomic or physiologic loss of function, and if an examinee presents with two or more sequential injuries and calculable impairments, the AMA Guides can be used to apportion between pre-existing and subsequent impairments. Courts often use the AMA Guides to decide statutorily determined benefits and are subject to interpretation by courts and administrative bodies whose interpretations may vary from state to state.

Download Full-text

Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2010.mayjun01 ◽

2010 ◽

Vol 15 (3) ◽

pp. 1-7

Author(s):

Richard T. Katz

Keyword(s):

Spinal Cord ◽

Spinal Cord Injuries ◽

Functional Independence ◽

Outcome Data ◽

Multiple Organ ◽

Loss Of Function ◽

Sixth Edition ◽

Organ Systems ◽

Cord Injury ◽

Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

Download Full-text

Letter to the Editor: The Continuing Challenge of Evaluating RSD Impairment and Disability

Guides Newsletter ◽

10.1001/amaguidesnewsletters.1998.sepoct05 ◽

1998 ◽

Vol 3 (5) ◽

pp. 8-10

Author(s):

Robert L. Knobler ◽

Charles N. Brooks ◽

Leon H. Ensalada ◽

James B. Talmage ◽

Christopher R. Brigham

Keyword(s):

Disability Evaluation ◽

Body Part ◽

Loss Of Function ◽

Regulatory Requirements ◽

Major Cardiac Event ◽

Clinical Scenarios ◽

Impairment Score ◽

Occupational Activities ◽

The Difference

Abstract The author of the two-part article about evaluating reflex sympathetic dystrophy (RSD) responds to criticisms that a percentage impairment score may not adequately reflect the disability of an individual with RSD. The author highlights the importance of recognizing the difference between impairment and disability in the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides): impairment is the loss, loss of use, or derangement of any body part, system, or function; disability is a decrease in or the loss or absence of the capacity to meet personal, social, or occupational demands or to meet statutory or regulatory requirements because of an impairment. The disparity between impairment and disability can be encountered in diverse clinical scenarios. For example, a person's ability to resume occupational activities following a major cardiac event depends on medical, social, and psychological factors, but nonmedical factors appear to present the greatest impediment and many persons do not resume work despite significant improvements in functional capacity. A key requirement according to the AMA Guides is objective documentation, and the author agrees that when physicians consider the disability evaluation of people, more issues than those relating to the percentage loss of function should be considered. More study of the relationships among impairment, disability, and quality of life in patients with RSD are required.

Download Full-text