| Full gene name: | notch 2 |
|---|---|
| Entrez Gene ID: | 4853 |
| Location: | 1p13-p11 |
| Synonyms: | AGS2, hN2, HJCYS |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs10923931 | 0 | within |
This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]
| OMIM ID: | `OMIM ID 600275 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 ALAGILLE SYNDROME 2
McDaniell et al. (2006) described a mother and son with Alagille syndrome (610205), both of whom had a splice acceptor mutation (5930-1G-A) in exon 33 of the NOTCH2 gene. The proband had cholestatic liver disease, cardiac disease characteristic facial features, and severe infantile renal disease. He died of cardiopulmonary arrest at age 2. His mother had valvular and peripheral pulmonic stenosis, characteristic facial features, and dysplastic kidneys and proteinuria that resulted in renal failure and a kidney transplant. The maternal grandparents and 3 of the mother’s sibs did not carry the mutation, indicating it was a de novo change in the proband’s mother.
.0002 ALAGILLE SYNDROME 2
In a proband, her mother, and her grandmother with Alagille syndrome (610205), McDaniell et al. (2006) identified a 1331G-A transition in exon 8 of the NOTCH2 gene that resulted in a cys444-to-tyr (C444Y) substitution in the eleventh EGF-like repeat of the protein.
.0003 HAJDU-CHENEY SYNDROME
In 3 affected members of a family with autosomal dominant Hajdu-Cheney syndrome, also known as acroosteolysis with osteoporosis and changes in the skull and mandible (102500), Simpson et al. (2011) identified a heterozygous 1-bp deletion (6272delT) in exon 34 of the NOTCH2 gene, resulting in a frameshift and premature truncation. The mutation occurred in the last exon of the NOTCH2 gene and escaped nonsense-mediated mRNA decay. RT-PCR studies showed that the truncated protein was expressed in patient fibroblasts. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function.
.0004 HAJDU-CHENEY SYNDROME
In 3 affected members of a family with autosomal dominant Hajdu-Cheney syndrome (102500), Simpson et al. (2011) identified a heterozygous 1-bp deletion (6460delT) in exon 34 of the NOTCH2 gene, resulting in a frameshift and premature truncation. The mutation occurred in the last exon of the NOTCH2 gene and likely escaped nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function.
.0005 HAJDU-CHENEY SYNDROME
In 3 affected members of a family with autosomal dominant Hajdu-Cheney syndrome (102500), Simpson et al. (2011) identified a heterozygous 6622C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2208-to-ter (Q2208X) substitution. The Q2208X mutation was also found in 2 affected members of a second unrelated family with Hajdu-Cheney syndrome. The mutation occurred in the last exon of the NOTCH2 gene and likely escaped nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function.
.0006 HAJDU-CHENEY SYNDROME
In 4 affected members of a family with autosomal dominant Hajdu-Cheney syndrome (102500), Isidor et al. (2011) identified a heterozygous 7119T-G transversion in exon 34 of the NOTCH2 gene, resulting in a tyr2373-to-ter (Y2373X) substitution. The mutation occurred in the last exon of the NOTCH2 gene and was expected to escape nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function.
.0007 HAJDU-CHENEY SYNDROME
In 2 affected members of a family with autosomal dominant acroosteolysis with osteoporosis and changes in the skull and mandible (102500), Isidor et al. (2011) identified a heterozygous 6949C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2317-to-ter (Q2317X) substitution. The mutation occurred in the last exon of the NOTCH2 gene and was expected to escape nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function.
.0008 HAJDU-CHENEY SYNDROME
In a girl with Hajdu-Cheney syndrome (102500), Gray et al. (2012) identified a heterozygous 6895G-T transversion in exon 34 of the NOTCH2 gene, resulting in a glu2299-to-ter (E2299X) substitution. The truncated protein was predicted to lack the PEST domain, leading to an increased level of NOTCH signaling in multiple tissues. The patient had originally been reported by Rosser et al. (1996) as having serpentine fibula-polycystic kidney syndrome. On follow-up by Gray et al. (2012) between ages 8 and 12 years, she showed mild developmental delay and progressive pulmonary disease requiring supplemental oxygen and corticosteroid treatment. Facial dysmorphism included narrow hirsute forehead, low posterior hairline, shallow supraorbital ridges, horizontal palpebral fissures, a convergent squint, a pinched nasal bridge with a wide nose, a small mouth, dental malocclusion, low-set posteriorly rotated ears, and prominent maxillae. She had short stature, acroosteolysis, osteoporosis, and stress fractures of the metatarsals bilaterally.
.0009 HAJDU-CHENEY SYNDROME
In a girl with Hajdu-Cheney syndrome (102500), Gray et al. (2012) identified a heterozygous 7165C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2389-to-ter (Q2389X) substitution. The truncated protein was predicted to lack the PEST domain, leading to an increased level of NOTCH signaling in multiple tissues. The patient was originally reported by Albano et al. (2007) as having serpentine fibula-polycystic kidney syndrome. At age 8 years, she had persistent ductus arteriosus, ventricular septal defect, and facial dysmorphism, including a thin upper lip, downturned mouth, wide nasal tip, long and flat philtrum, dysplastic and posteriorly rotated ears, and short neck. She had bilateral sensorineural hearing loss. Skeletal studies showed wormian bones, vertebral abnormalities, and serpentine fibulae. Ultrasound examination showed polycystic kidneys, but renal function was normal. At age 18 years, she had short stature, hypothyroidism, bathrocephaly, and irregular tooth positioning. There was no significant acroosteolysis of the hands or feet, but she had mild thinning of the distal phalanges. Brain MRI scan showed basilar invagination and abnormal curvature of the cervical spine without cord compression. Intelligence was normal.
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