Alternative titles; symbols
HGNC Approved Gene Symbol: NDE1
SNOMEDCT: 1237462006;
Cytogenetic location: 16p13.11 Genomic coordinates (GRCh38): 16:15,643,382-15,726,353 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.11 | Lissencephaly 4 (with microcephaly) | 614019 | Autosomal recessive | 3 |
| Microhydranencephaly | 605013 | Autosomal recessive | 3 |
The NDE1 gene encodes a protein with a role in mitosis. NDE1 and LIS1 (PAFAH1B1; 601545) interact and are involved in cerebral cortical development (Bakircioglu et al., 2011; Feng and Walsh, 2004; Pawlisz et al., 2008).
Using Lis1 as bait in a yeast 2-hybrid screen of a rat liver cDNA library, Kitagawa et al. (2000) cloned rat Nude. The deduced 344-amino acid protein contains an asp- and glu-rich N-terminal half and a ser- and thr-rich C-terminal half. Rat Nude shares significant homology with a fungal nuclear distribution protein, NudE, and a Xenopus mitotic phosphoprotein, Mpp43. Northern blot analysis detected a 2.4-kb Nude transcript in all rat tissues examined.
By subtractive hybridization to isolate testis-specific transcripts, followed by serologic expression screening with antibodies from a seminoma patient, Tureci et al. (2002) isolated NDE1, which they designated HOM-TES-87. Northern blot analysis detected high expression in testis, and RT-PCR detected NDE1 in other tissues.
By PCR of a placenta cDNA library, Yan et al. (2003) cloned human NUDE. Western blot analysis detected NUDE at an apparent molecular mass of about 40 kD in several human cell lines. Western blot analysis of mouse tissues detected highest expression in brain, with much lower expression in heart, skeletal muscle, and lung, and little to no expression in other tissues examined.
Bakircioglu et al. (2011) found NDE1 expression in the apical neuroepithelium throughout the developing human and mouse brain. NDE1 was strongly expressed in apical precursors in the ventricular zone and in the newborn neuronal population of the human embryonic brain, but had reduced expression in the subventricular zone. In the mouse brain, Nde1 localized to the centrosomes of all cells. In apical neuroepithelial cells, expression of centrosomal Nde1 was greatest during interphase and early mitosis and reduced during metaphase. In cultured cells, Nde1 colocalized with gamma-tubulin (TUBG1; 191135) at the centrosome and was present in the cytoplasm, at the centrosome, and on the mitotic spindle.
The NDE1 gene contains 9 exons, the last of which is entirely contained in the neighboring MYH11 gene (160745) (Bakircioglu et al., 2011).
Bakircioglu et al. (2011) noted that the NDE1 gene maps to chromosome 16p13.
Kitagawa et al. (2000) found that rat Nude and the catalytic subunits of Pafah (see PAFAH1B2; 602508) interacted with Pafah1b1 in a competitive manner. They suggested that PAFAH1B1 functions in nuclear migration by interacting with multiple intracellular proteins, including NUDE.
Yan et al. (2003) found that NUDE was phosphorylated in M phase of the cell cycle in human cells. A fraction of NUDE bound strongly to centrosomes in interphase and localized to mitotic spindles in early M phase. ATP inhibitor assays indicated that NUDE bound cytoplasmic dynein (see 600112) and migrated with it to spindle poles along microtubules.
Burdick et al. (2008) noted that NDE1 is a homolog of NDEL1 (607538) and also binds to DISC1 (605210). NDE1 was expressed at constant levels in the rat cerebral cortex from embryonic day (E) 14 to adulthood, whereas NDEL1 expression showed a time-course increase peaking at postnatal day 7. Further studies with a ser704-to-cys (S704C) polymorphism in the DISC1 gene showed that NDE1 bound stronger to ser704, while NDEL1 bound stronger to cys704. The findings suggested an interaction of these 3 proteins, with possible competitive binding between NDEL1 and NDE1 for DISC1.
Alkuraya et al. (2011) demonstrated the NDE1 is phosphorylated by CDK1 (116940) and that phosphorylation of NDE1 at thr246 in the C-terminal domain is required for cells to progress through the G2/M phase of mitosis.
Lissencephaly 4
By linkage analysis followed by candidate gene sequencing, Bakircioglu et al. (2011) identified 2 different homozygous truncating mutations in the NDE1 gene (609449.0001 and 609449.0002, respectively) in affected members of 3 consanguineous families with lissencephaly-4 (LIS4; 614019) with extreme microcephaly. The disorder showed dual pathogenesis of profound early prenatal failure of neuron production and later prenatal deficiency of cortical lamination.
Alkuraya et al. (2011) independently identified 2 homozygous truncating mutations in the NDE1 gene (609449.0001 and 609449.0003, respectively) in affected members from 2 consanguineous Saudi Arabian families with LIS4. Patient-derived lymphoblast cells showed spindle-structure defects, including tripolar spindles, misaligned mitotic chromosomes, nuclear fragmentation, and abnormal microtubule organizations, supporting an essential role for NDE1 in normal mitotic spindle function, neuronal proliferation, and human cerebral cortical neurogenesis.
In 2 sibs, one with hydranencephaly (MHAC; 605013) and the other with LIS4, who were born to nonconsanguineous parents from Egypt, Abdel-Hamid et al. (2019) identified a homozygous nonsense mutation in exon 2 of the NDE1 gene (W18X; 609449.0005). Another sib with microlissencephaly died before molecular analysis was performed. Both parents were heterozygous for the variant, which was not found in public variant databases.
Microhydranencephaly
In 2 cousins, born of consanguineous Turkish parents, with microhydranencephaly (MHAC; 605013), Guven et al. (2012) identified a homozygous intragenic deletion in the NDE1 gene (609449.0004). The mutation was predicted to result in a completely null allele, but functional studies were not performed. The patients had extreme microcephaly, profound motor and mental retardation, spasticity, and incomplete cerebral formation. Radiologic studies showed gross dilation of the ventricles resulting from the absence of cerebral hemispheres or severe delay in their development, as well as hypoplasia of the corpus callosum, cerebellum, and brainstem. Guven et al. (2012) noted that the MHAC phenotype is more severe than that observed in patients with LIS4, thus expanding the spectrum of clinical features associated with NDE1 mutations.
In 2 sibs, one with MHAC and the other with LIS4, who were born to nonconsanguineous parents from Egypt, Abdel-Hamid et al. (2019) identified a homozygous nonsense mutation in exon 2 of the NDE1 gene (W18X; 609449.0005). Another sib with microlissencephaly died before molecular analysis was performed. Both parents were heterozygous for the variant, which was not found in public variant databases. The authors noted that pathogenic variants in NDE1 are involved in a broad spectrum of brain malformations and that the combination of severe microcephaly, early-onset epilepsy, lissencephaly and/or hydranencephaly should raise suspicion of the involvement of the NDE1 gene.
Feng and Walsh (2004) found that Nde1-null mice were viable, but they showed a small-brain phenotype. At 6 to 8 weeks of age, the brains of Nde1-null mice were one-third smaller than their wildtype or heterozygous counterparts. The size reduction predominantly affected the cerebral cortex, while other brain structures, including the hippocampus, midbrain, and cerebellum, appeared normal or were only slightly reduced in size. Cortical lamination was mostly preserved, but the mutant cortex had fewer neurons and thin superficial cortical layers II to IV. Bromodeoxyuridine birthdating revealed retarded and modestly disorganized neuronal migration. More dramatic defects were found in mitotic progression, mitotic orientation, and chromosome localization in cortical progenitors. The small cerebral cortex of Nde1-null mice appeared to reflect both reduced progenitor cell division and altered neuronal cell fates. In vitro analysis demonstrated that Nde1 was essential for centrosome duplication and mitotic spindle assembly. Feng and Walsh (2004) concluded that mitotic spindle function and orientation are essential for normal cortical development.
Interaction between Nde1 and Lis1 is critical in the development of the mouse central nervous system (CNS). Pawlisz et al. (2008) analyzed a series of Nde1 and Lis1 double mutations in mice and showed that the Nde1-Lis1 complex was specifically required by the radial glial/neuroepithelial progenitor cells during CNS development. Besides mitotic spindle regulation, Lis1 and Nde1 maintained the morphology and lateral cell-cell contacts of progenitors in the cortical ventricular zone. This cell shape and organization control appeared necessary for symmetrical cell division and the self-renewal of neural progenitors during the early phase of corticogenesis. Loss of Lis1-Nde1 function led to dramatically increased neuronal differentiation at the onset of cortical neurogenesis, resulting in overproduction of the earliest-born preplate and Cajal-Retzius neurons, with consequent loss of the laminar pattern and over 80% mass and surface area of the cerebral cortex.
Alkuraya et al. (2011) found that mouse embryonic fibroblasts with Nde1 mutations showed defects in mitotic progression, as evidenced by an increased mitotic index; abnormal spindle structures such as multipolar spindles; and chromosome misalignment.
In affected members of 2 unrelated consanguineous Pakistani families with lissencephaly-4 (LIS4; 614019) with extreme microcephaly, Bakircioglu et al. (2011) identified a homozygous 2-bp deletion (684delAC) in exon 6 of the NDE1 gene, resulting in a frameshift, loss of amino acids 229 to 335, addition of 84 novel amino acids, and ultimately termination at position 314. The mutant protein was predicted to lack the highly conserved C-terminal domain, which is critical for localization to the centrosome. In vitro functional expression studies showed that the mutant protein failed to localize properly to the centrosome. Haplotype analysis indicated a founder effect.
Alkuraya et al. (2011) identified a homozygous 684delAC mutation in 2 sisters, born of consanguineous Saudi Arabian parents, with LIS4. Immunoblot analysis of patient lymphocytes showed no detectable NDE1 expression, suggesting that the mutant protein was unstable and subject to degradation. In vitro functional expression studies showed that the mutant protein could not bind dynein (see 600112), although LIS1 (601545) binding was normal.
In affected members of a consanguineous Turkish family with lissencephaly-4 (LIS4; 614019), Bakircioglu et al. (2011) identified a homozygous G-to-T transversion (83+1G-T) in the second exon donor site of the NDE1 gene. The mutation was shown to result in a frameshift beginning in exon 3, addition of 113 novel amino acids, and a premature stop codon at position 114. The resultant protein would lack the highly conserved C-terminal domain as well as the homodimerization domain. Immunoblot analysis showed significantly reduced NDE1 protein in patient cells compared to controls. In vitro functional expression studies showed that the mutant protein failed to colocalize properly with gamma-tubulin (TUBG1; 191135) and failed to localize to the centromere.
In affected members of a consanguineous Saudi Arabian family with lissencephaly-4 (LIS4; 614019), Alkuraya et al. (2011) identified a homozygous 1-bp duplication (733dupC) in exon 7 of the NDE1 gene, predicted to result in a truncated protein after the addition of 69 novel amino acids. The mutant protein lacked the conserved C-terminal domain critical for centromere localization. In vitro functional expression studies showed that the mutant protein could not bind dynein (see 600112), although LIS1 (601545) binding was normal. In addition, the mutant protein did not localize properly to the centrosome.
In 2 cousins, born of consanguineous Turkish parents, with microhydranencephaly (MHAC; 605013) (Kavaslar et al., 2000), Guven et al. (2012) identified a homozygous 4,296-bp deletion in the NDE1 gene (c.-43-3548_83+622del, chr16.15,755,045-15,759,340, GRCh37), predicted to remove from the region 43 nucleotides in exon 2 upstream of the initiation codon, the initiation codon itself, and 83 nucleotides downstream of it, including the first coding exon. The mutation, which segregated with the disorder in the family, was not found in 109 control individuals from the population. The mutation was predicted to result in a completely null allele, but functional studies were not performed.
In 2 sibs with brain malformations, one with microhydranencephaly (MHAC; 605013) and the other with lissencephaly (LIS4; 614019), who were born to nonconsanguineous parents from Egypt, Abdel-Hamid et al. (2019) identified a c.54G-A transition (c.54G-A, NM_017668) in exon 2 of the NDE1 gene, resulting in a trp18-to-ter (W18X) substitution. A third sib with microlissencephaly died before molecular analysis was performed. Both parents were heterozygous for the mutation, which was not present in the dbSNP, 1000 Genomes Project, ExAC, and gnomAD databases. No functional studies were reported.
Abdel-Hamid, M. S., El-Dessouky, S. H., Ateya, M. I., Gaafar, H. M., Abdel-Salam, G. M. H. Phenotypic spectrum of NDE1-related disorders: from microlissencephaly to microhydranencephaly. Am. J. Med. Genet. 179A: 494-497, 2019. [PubMed: 30637988] [Full Text: https://doi.org/10.1002/ajmg.a.61035]
Alkuraya, F. S., Cai, X., Emery, C., Mochida, G. H., Al-Dosari, M. S., Felie, J. M., Hill, R. S., Barry, B. J., Partlow, J. N., Gascon, G. G., Kentab, A., Jan, M., Shaheen, R., Feng, Y., Walsh, C. A. Human mutations in NDE1 cause extreme microcephaly with lissencephaly. Am. J. Hum. Genet. 88: 536-547, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 677 only, 2011. [PubMed: 21529751] [Full Text: https://doi.org/10.1016/j.ajhg.2011.04.003]
Bakircioglu, M., Carvalho, O. P., Khurshid, M., Cox, J. J., Tuysuz, B., Barak, T., Yilmaz, S., Caglayan, O., Dincer, A., Nicholas, A. K., Quarrell, O., Springell, K., and 11 others. : The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. Am. J. Hum. Genet. 88: 523-535, 2011. [PubMed: 21529752] [Full Text: https://doi.org/10.1016/j.ajhg.2011.03.019]
Burdick, K. E., Kamiya, A., Hodgkinson, C. A., Lencz, T., DeRosse, P., Ishizuka, K., Elashvili, S., Arai, H., Goldman, D., Sawa, A., Malhotra, A. K. Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: evidence of epistasis and competitive binding. Hum. Molec. Genet. 17: 2462-2473, 2008. [PubMed: 18469341] [Full Text: https://doi.org/10.1093/hmg/ddn146]
Feng, Y., Walsh, C. A. Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron 44: 279-293, 2004. [PubMed: 15473967] [Full Text: https://doi.org/10.1016/j.neuron.2004.09.023]
Guven, A., Gunduz, A., Bozoglu, T. M., Yalcinkaya, C., Tolun, A. Novel NDE1 homozygous mutation resulting in microhydranencephaly and not microlyssencephaly (sic). Neurogenetics 13: 189-194, 2012. [PubMed: 22526350] [Full Text: https://doi.org/10.1007/s10048-012-0326-9]
Kavaslar, G. N., Onengut, S., Derman, O., Kaya, A., Tolun, A. The novel genetic disorder microhydranencephaly maps to chromosome 16p13.3-12.1. Am. J. Hum. Genet. 66: 1705-1709, 2000. [PubMed: 10762554] [Full Text: https://doi.org/10.1086/302898]
Kitagawa, M., Umezu, M., Aoki, J., Koizumi, H., Arai, H., Inoue, K. Direct association of LIS1, the lissencephaly gene product, with a mammalian homologue of a fungal nuclear distribution protein, rNUDE. FEBS Lett. 479: 57-62, 2000. [PubMed: 10940388] [Full Text: https://doi.org/10.1016/s0014-5793(00)01856-1]
Pawlisz, A. S., Mutch, C., Wynshaw-Boris, A., Chenn, A., Walsh, C. A., Feng, Y. Lis1-Nde1-dependent neuronal fate control determines cerebral cortical size and lamination. Hum. Molec. Genet. 17: 2441-2445, 2008. [PubMed: 18469343] [Full Text: https://doi.org/10.1093/hmg/ddn144]
Tureci, O., Sahin, U., Koslowski, M., Buss, B., Bell, C., Ballweber, P., Zwick, C., Eberle, T., Zuber, M., Villena-Heinsen, C., Seitz, G., Pfreundschuh, M. A novel tumour associated leucine zipper protein targeting to sites of gene transcription and splicing. Oncogene 21: 3879-3888, 2002. [PubMed: 12032826] [Full Text: https://doi.org/10.1038/sj.onc.1205481]
Yan, X., Li, F., Liang, Y., Shen, Y., Zhao, X., Huang, Q., Zhu, X. Human Nudel and NudE as regulators of cytoplasmic dynein in poleward protein transport along the mitotic spindle. Molec. Cell. Biol. 23: 1239-1250, 2003. [PubMed: 12556484] [Full Text: https://doi.org/10.1128/MCB.23.4.1239-1250.2003]