Notch Receptor 3

Alternative Names

  • NOTCH3
  • NOTCH, Drosophila, Homolog of, 3
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OMIM Number

600276

NCBI Gene ID

4854

Uniprot ID

Q9UM47

Length

41,958 bases

No. of Exons

33

No. of isoforms

1

Protein Name

Neurogenic locus notch homolog protein 3

Molecular Mass

243631 Da

Amino Acid Count

2321

Genomic Location

chr19:15,159,038-15,200,995

Gene Map Locus
19p13.2-p13.1

Description

The NOTCH gene in Drosophila codes for a membrane bound receptor, which interacts with certain ligands and transduces signals that affect key processes in neural development. NOTCH3 is the third discovered human homologue of this gene. Similarly, homologues of the Drosphila NOTCH ligand have also been observed in humans, such as Jagged1, Jagged2, and Delta1. However, the exact nature of the interaction between the human NOTCH protein and these ligands has not been understood. By homology modeling and similarity studies, it seems that the NOTCH protein is a membrane bound receptor that is activated by the binding of the above-mentioned ligands. This activation causes the cleavage of the receptor to release a peptide fragment containing the intracellular domain fragment. This leads to the formation of a transcriptional activator complex involving RBP-J kappa, which further activates genes involved in the cell cycle, mainly in the differentiation, proliferation, and apoptotic mechanisms of the cell.

Autosomal dominant mutations in the NOTCH3 gene have been shown to be the cause of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a disorder characterized by recurrent transient ischemic attacks and vascular dementia.

Molecular Genetics

The NOTCH3 gene is located on the short arm of chromosome 19, where it spans a length of about 42Kb. The gene is made up of 33 exons. The protein this gene codes for, weighs less than 25 kDa, and is made up of 2321 amino acids. The protein is in an inactive form when it is first synthesized in the ER. Post-translational modifications, including protelolytic cleavage, yield a mature protein with a c-terminal and an N-terminal fragment, held together by disulfide bonds. This protein is expressed mainly in vascular smooth cells.

In patients with CADASIL, most mutations in the NOTCH3 gene have been found to missense, incorporating the loss or gain of a cysteine residue. To date, all mutations have been found to cluster in regions of the gene that code for the epidermal growth factor repeats in the extracellular part of the protein. Thus, most mutations have been observed in exons 3 and 4.

Epidemiology in the Arab World

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Variant NameCountryGenomic LocationClinical SignificanceCondition(s)HGVS ExpressionsdbSNPClinvar
NM_000435.2:c.3691C>TUnited Arab EmiratesNC_000019.10:g.15179052G>ALikely Pathogenic,Uncertain SignificanceCerebral Arteriopathy, Autosomal Dominant, with Subcortical Infarcts and LeukoencephalopathyNG_009819.1:g.26930C>T; NM_000435.2:c.3691C>T; NP_000426.2:p.Arg1231Cys201680145216972
NM_000435.3:c.1369T>CLebanonchr19:15188998Likely PathogenicCerebral Arteriopathy, Autosomal Dominant, with Subcortical Infarcts and LeukoencephalopathyNG_009819.1:g.16984T>C; NM_000435.3:c.1369; NP_000426.2:p.Cys457Arg
NM_000435.3:c.4581_4594delUnited Arab EmiratesNC_000019.10:g.15174213_15174226delLikely PathogenicCerebral Arteriopathy, Autosomal Dominant, with Subcortical Infarcts and LeukoencephalopathyNG_009819.1:g.31759_31772del; NM_000435.3:c.4581_4594del; NP_000426.2:p.Ser1528AlafsTer30

Other Reports

Iraq

Mignarri et al. (2011) reported a 54-year-old Iraqi Kurdish male with CADASIL. Mutational analysis of his NOTCH3 gene uncovered the c.3691C>T (p.Arg1231Cys) mutation in exon 22.

Kuwait

Bohlega et al. (2007) undertook molecular studies on a Kuwaiti family diagnosed with CADASIL. Sequencing of the NOTCH3 gene revealed the presence of a previously reported heterozygous c.406C>T (p.Arg110>Cys) pathogenic mutation. This mutation was not detected in 100 ethnically matched controls.

[See also: Saudi Arabia, Yemen > Bohlega et al., 2007].

Saudi Arabia

Sequencing of the NOTCH3 gene in a Saudi family diagnosed with CADASIL revealed the presence of a previously reported heterozygous c.406C>T (p.Arg110>Cys) pathogenic mutation (Bohlega et al. 2007). This mutation was not detected in 100 ethnically matched controls. The same mutation was also detected in a Kuwaiti family in the same study. Abu-Amero et al. (2008) expanded this study with the addition of another Saudi affected pedigree. The index case in this family was found to have a c.1568C>T mutation in the NOTCH3 gene.

[See also: Kuwait > Bohlega et al., 2007; Abu-Amero et al., 2008].

Sudan

Abu-Amero et al. (2008) undertook a study to understand the reported association of CADASIL with mitochondrial abnormalities. The patient cohort included a Sudanese family affected with CADASIL. Interestingly, Abu-Amero et al. (2008) were not able to detect any mutation in the NOTCH3 gene in the index case in this family.

Yemen

Bohlega et al. (2007) detected a previously reported heterozygous c.475C>T (p.Arg113>Cys) pathogenic mutation in the NOTCH3 gene in a Yemeni family affected with CADASIL. This mutation was not detected in 100 ethnically matched controls.

[See also: Kuwait > Bohlega et al., 2007].

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