NDE1
protein-codingnudE neurodevelopment protein 1, the group of MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~91.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013527
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013527
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0700116
Submitter: ClinGen
The relationship between *NDE1* and microcephaly with lissencephaly and/or hydranencephaly was first reported in 2011 (PMID: 21529752, PMID: 21529751). Microcephaly with lissencephaly and/or hydranencephaly is a brain disorder that is characterized by extreme microcephaly (typically head circumference of less than 10 standard deviations (SD) below the mean), profound motor and intellectual disability, spasticity, and incomplete cerebral formation. Patients demonstrate cortical dysgenesis ranging from simplification to pachygyria/lissencephaly to hydranencephaly. Agenesis of the corpus callosum as well as hypoplasia of the brainstem and cerebellum are typically present. These presentations were lumped into a single disease curation, consistent with shared molecular mechanism and mode of inheritance (Autosomal Recessive, AR). At least 8 variants in *NDE1* have been identified in individuals with microcephaly with lissencephaly and/or hydranencephaly over 14 years (PMID: 21529751, 34562061,21529752, 22526350, 30637988, 29191162, 23704059). These variants include loss of function and missense variants in highly conserved residues. In the literature, patients with severe microcephaly have been identified with deletions of 16p13.11 (including *NDE1*) and an additional *NDE1* variant on the second allele (PMID: 23704059, PMID: 29191162). Due to the prominent phenotype, these cases have been scored. More evidence is available in the literature, but the maximum genetic evidence (12 pts) was reached. This gene-disease relationship is also supported by animal models and in vitro data. *NDE1* was first associated with cerebral cortical size in 2004 (PMID: 15473967). Initially, *NDE1* was identified as a *LIS1* interacting protein (PMID: 11163258). *NDE1* is part of a multiprotein complex that regulates dynein function, playing an essential role in microtubule organization, mitosis and neuronal migration. Experimental data from mouse and yeast studies supports the role of *NDE1* in brain malformation. *NDE1* is strongly expressed in the developing mouse cerebral cortex (PMID: 11163258). Null mouse models of *NDE1* demonstrate neuronal migration defects, resulting in microcephaly, including fewer neurons and a thin superficial cortical layer (PMID: 15473967). In summary, there is definitive evidence supporting the relationship between *NDE1* and microcephaly with lissencephaly and/or hydranencephaly. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Brain Malformation GCEP on December 10, 2024 (SOP 11).
Inheritance Pattern: AR
Disease ID:MONDO:0016344
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0015204
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011504
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0700116
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013527
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013527
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: Unknown
Disease ID:MONDO:0011504
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NDE1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017668.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 49 | 1 | 57 | ||
| missense | 1 | 104 | 6 | 111 | ||
| nonsense | 3 | 2 | 3 | 8 | ||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 1 | 1 | 5 | ||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 2 | 5 | ||
| Total | 8 | 6 | 117 | 55 | 1 | 187 |
Highest pathogenic variant AF is 0.000058242127
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060138.1 | 8 | MANE Select | |
| Ensembl | ENSP00000379642.1 | 8 | MANE Select | |
| RefSeq | NP_001137451.1 | 8 | Standard | |
| Ensembl | ENSP00000379643.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nde1 | Danio rerio | Structure: head Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
- Amplification of signal from the kinetochores
- Mitotic Spindle Checkpoint
- Cell Cycle Checkpoints
Biological Process
- G2/M transition of mitotic cell cycle
- establishment of mitotic spindle orientation
- neuron migration
- microtubule nucleation
- chromosome segregation
Molecular Function
- protein binding
- microtubule binding
- protein domain specific binding
- identical protein binding
Cellular Component
- kinetochore
- condensed chromosome kinetochore
- centrosome
- cytosol
- kinesin complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396355
- Coding exons
- 8
- Length
- 83087
- Individuals with no LoFs
- 125713
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 34
- Defined
- 125747
- p
- 0.000135
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.13 | 246 | 201 | 1.22 | 0.0000140 | 2175 |
| Missense (PolyPhen) | 45 | 48.219 | 0.93324 | 591 | ||
| Synonymous | -1.35 | 99 | 83.3 | 1.19 | 0.00000603 | 652 |
| Loss of Function | 2.56 | 7 | 19.1 | 0.367 | 0.00000120 | 210 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for centrosome duplication and formation and function of the mitotic spindle. Essential for the development of the cerebral cortex. May regulate the production of neurons by controlling the orientation of the mitotic spindle during division of cortical neuronal progenitors of the proliferative ventricular zone of the brain. Orientation of the division plane perpendicular to the layers of the cortex gives rise to two proliferative neuronal progenitors whereas parallel orientation of the division plane yields one proliferative neuronal progenitor and a post- mitotic neuron. A premature shift towards a neuronal fate within the progenitor population may result in an overall reduction in the final number of neurons and an increase in the number of neurons in the deeper layers of the cortex. {ECO:0000269|PubMed:17600710, ECO:0000269|PubMed:21529752}.;
- Disease
- DISEASE: Lissencephaly 4 (LIS4) [MIM:614019]: A neurodevelopmental disorder characterized by lissencephaly, severe brain atrophy, extreme microcephaly, and profound mental retardation. {ECO:0000269|PubMed:21529751, ECO:0000269|PubMed:21529752}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Microhydranencephaly (MHAC) [MIM:605013]: A severe neurodevelopmental disorder characterized by microcephaly, severe motor and mental retardation, spasticity, and brain malformations that include gross dilation of the ventricles with complete absence of the cerebral hemispheres or severe delay in their development. {ECO:0000269|PubMed:22526350}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.169
Intolerance Scores
- LoFtool
- 0.135
- RVIS EVS
- -0.82
- RVIS percentile EVS
- 11.77
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.824
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |