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NDP
norrin cystine knot growth factor NDP
The NDP gene provides instructions for making the norrin protein, which is crucial for normal eye development, particularly retinal specialisation and blood vessel formation in the retina and inner ear. The NDP gene encodes the norrin protein, a signalling molecule vital for cellular development and communication.
NDP is located on the short (p) arm of chromosome X, at band Xp11.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The NDP gene, located on the X chromosome, is responsible for producing the norrin protein. This protein plays a key role in various cellular processes, particularly those involved in the development of the eye and other body systems. Norrin is a ligand that interacts with specific receptors to initiate signalling pathways essential for cell division, adhesion, and migration.
Disruptions to the NDP gene's function can lead to several inherited eye conditions, primarily affecting the retina and its vascular development. These conditions range in severity, from progressive vision loss to profound blindness.
What the gene does
The norrin protein, encoded by the NDP gene, acts as a signalling molecule within cells. It participates in pathways that influence cell and tissue development, with studies suggesting its involvement in Wnt signalling. This pathway is fundamental for diverse cellular activities, including proliferation, cell-to-cell adhesion, and migration.
Norrin functions by binding to frizzled receptors, particularly frizzled-4 (encoded by the FZD4 gene), which are embedded in cell membranes. This interaction, much like a key fitting into a lock, triggers a multi-step process that regulates the activity of specific genes. This mechanism is critical for the proper development of the eye, especially for the specialisation of retinal cells and the formation of blood vessels within both the retina and the inner ear.
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Chromosome location
The NDP gene is situated on the short arm of the X chromosome at position 11.3, denoted as Xp11.3. This genomic location means that the gene follows an X-linked inheritance pattern. The protein encoded by NDP consists of 133 amino acids.
Protein structure
The norrin protein is 133 amino acids long and contains a distinct protein domain. The CTCK (cystine knot growth factor) domain spans amino acids 39-132, which is characteristic of certain growth factors and involved in protein stability and receptor binding.
Key variants
Variants within the NDP gene can impact the structure and function of the norrin protein, leading to a range of clinical presentations. These genetic changes can alter single protein building blocks or affect how the norrin protein folds and interacts with its target receptors. The severity and specific symptoms depend on the nature and location of the variant.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in the NDP gene are primarily associated with inherited disorders affecting the eye. These conditions include Norrie disease, a severe X-linked recessive disorder leading to blindness, and Familial Exudative Vitreoretinopathy, which can cause progressive vision loss. Other retinal disorders such as Persistent Hyperplastic Primary Vitreous may also be linked to NDP variants, resulting in various degrees of visual impairment.
Inheritance pattern
Conditions caused by pathogenic NDP variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
The NDP gene is included in several UK NHS Genomic Medicine Service national test directories, indicating its clinical significance. It is part of panels for conditions such as Bilateral congenital or childhood onset cataracts, Foetal anomalies, Intellectual disability, Retinal disorders, and Structural eye disease, demonstrating its relevance in diagnosing a wide range of developmental and ophthalmological conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the norrin protein?
The norrin protein, encoded by the NDP gene, is a signalling molecule that plays a critical role in cellular development, particularly in the formation of blood vessels and the specialisation of cells in the retina and inner ear. It activates specific cell surface receptors to regulate gene activity.
What inherited conditions are associated with NDP gene variants?
Variants in the NDP gene are primarily linked to inherited eye disorders such as Norrie disease, which causes severe vision impairment or blindness, and Familial Exudative Vitreoretinopathy, characterised by progressive vision loss. Other retinal conditions, including Persistent Hyperplastic Primary Vitreous, may also be associated.
How is the NDP gene inherited?
The NDP gene is located on the X chromosome, meaning it follows an X-linked inheritance pattern. This typically means that males are more severely affected by pathogenic variants due to having only one X chromosome, while females may be carriers or experience milder symptoms depending on X-inactivation.
References
- Shastry BS. Genetic susceptibility to advanced retinopathy of prematurity (ROP). Journal of biomedical science. 2010. PMID: 20738858
- Kondo H, Qin M, Kusaka S. Novel mutations in Norrie disease gene in Japanese patients with Norrie disease and familial exudative vitreoretinopathy. Investigative ophthalmology & visual science. 2007. PMID: 17325173
- Dickinson JL, Sale MM, Passmore A. Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clinical & experimental ophthalmology. 2006. PMID: 16970763
- Xu Q, Wang Y, Dabdoub A. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004. PMID: 15035989
- Clevers H. Wnt signaling: Ig-norrin the dogma. Current biology : CB. 2004. PMID: 15182694
- Royer G, Hanein S, Raclin V. NDP gene mutations in 14 French families with Norrie disease. Human mutation. 2003. PMID: 14635119
- Haider MZ, Devarajan LV, Al-Essa M. A C597-->A polymorphism in the Norrie disease gene is associated with advanced retinopathy of prematurity in premature Kuwaiti infants. Journal of biomedical science. 2002. PMID: 12145535
- Hiraoka M, Berinstein DM, Trese MT. Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity. Journal of human genetics. 2001. PMID: 11322656
- Adam MP, Bick S, Mirzaa GM. NDP-Related Retinopathies. 1993. PMID: 20301506
- Chen ZY, Hendriks RW, Jobling MA. Isolation and characterization of a candidate gene for Norrie disease. Nature genetics. 1992. PMID: 1303236