Alternative titles; symbols
HGNC Approved Gene Symbol: NDP
SNOMEDCT: 15228007;
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38): X:43,948,776-43,973,390 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.3 | Exudative vitreoretinopathy 2, X-linked | 305390 | X-linked dominant; X-linked recessive | 3 |
| Norrie disease | 310600 | X-linked recessive | 3 |
The NDP gene encodes norrin, a secreted cysteine-rich protein that belongs to the cystine knot growth factor family (Meindl et al., 1992).
By positional cloning, Berger et al. (1992) and Chen et al. (1992) isolated a likely candidate gene for the site of mutation in Norrie disease (ND; 310600). The gene was found to be expressed in retina, choroid, and fetal brain by Berger et al. (1992) and in fetal and adult brain by Chen et al. (1992). It was evolutionarily conserved and encoded a predicted protein of 133 amino acids. The genomic equivalent of the cDNA spanned a maximum of 50 kb (Chen et al., 1992) and was partly deleted in several typical Norrie disease patients.
By studying the number and spacing of cysteine residues, Meindl et al. (1992) detected homologies between the NDP gene product and a C-terminal domain that is common to a group of proteins including mucins.
Chen et al. (1993) found that expression of the NDP gene is not confined to the eye or to the brain. They found homology with cysteine-rich protein-binding domains of intermediate-early genes implicated in the regulation of cell proliferation. This led them to propose that the NDP molecule likewise may be involved in the pathway that regulates neural cell differentiation and proliferation.
Meitinger et al. (1993) reported that sequence pattern searches and 3-dimensional modeling suggested that the NDP protein has a tertiary structure similar to that of transforming growth factor-beta (see TGFB1, 190180). The model identified NDP as a member of an emerging family of growth factors containing a cystine knot motif, with direct implications for the physiologic role of NDP.
Berger et al. (1996) cloned the mouse Ndp gene, which encodes a polypeptide that shares 94% sequence identity with the human protein. RNA in situ hybridization revealed expression in retina, brain, and olfactory bulb and epithelium of 2-week-old mice.
Meindl et al. (1992) found that only exons 2 and 3 of the NDP gene are translated. Exon 2 contains the first 58 codons of the open reading frame. The intron that follows it is roughly 14.5 kb. Exon 3 is the largest exon and contains residues 59-133 of the open reading frame and a 917-bp 3-prime untranslated region.
Chen et al. (1993) determined that the NDP gene spans 28 kb and contains 3 exons, the first of which is entirely contained within the 5-prime untranslated region.
Sims et al. (1992) narrowed the mapping of the NDP gene to a 150-kb region on chromosome Xp defined by a recombination and by the smallest submicroscopic chromosomal deletion associated with Norrie disease. They concluded that the order of loci was: pter--DXS7--MAOA--MAOB--NDP--cen.
Berger et al. (1996) mapped the mouse Ndp gene to the X chromosome.
In studies in COS-7 cells, Perez-Vilar and Hill (1997) found that norrin was present only in cell lysates and the extracellular matrix. Further analysis showed that most of the norrin in the extracellular matrix formed cross-linked disulfide-bonded oligomers that contained up to 20 monomers.
By in situ hybridization of NDP mRNA, Hartzer et al. (1999) found abundant signals in the outer nuclear, inner nuclear, and ganglion cell layers of the retina in all 3 species (mouse, rabbit, and human) examined. There was no significant expression in the vitreous humor, lens, or rod outer segment. High expression levels were also observed in the cerebellar granular layer, hippocampus, olfactory bulb, cortex, and epithelium of the rabbit brain. These data suggested that the NDP gene could play a critical role in the differentiation or maintenance of the differentiated state of the retina.
Incomplete retinal vascularization occurs in both Norrie disease and familial exudative vitreoretinopathy (FEVR). One form of FEVR (EVR1; 133780) is caused by defects in frizzled-4 (FZD4; 604579), a presumptive Wnt receptor. Xu et al. (2004) determined that norrin and FZD4 function as a ligand-receptor pair based on the similarity in vascular phenotypes caused by norrin and FZD4 mutations in humans and mice; the specificity and high affinity of norrin-FZD4 binding; the high efficiency with which norrin induces FZD4- and LRP (see 107770)-dependent activation of the classic Wnt pathway; and the signaling defects displayed by disease-associated variants of norrin and FZD4. These data defined a norrin-FZD4 signaling system that plays a central role in vascular development in the eye and ear, and they indicated that ligands unrelated to Wnts can act through frizzled receptors.
Norrie Disease
Berger et al. (1992) identified small deletions in the NDP gene in several patients with Norrie disease. In 12 of 17 unrelated patients with Norrie disease, Berger et al. (1992) identified 11 different mutations in the NDP gene (see, e.g., 300658.0001-300658.0002). Most of the mutations were located in exon 3.
In 3 unrelated patients with Norrie disease, Meindl et al. (1992) identified 3 missense mutations in the NDP gene (300658.0003-300658.0005). All 3 mutations replaced evolutionarily conserved cysteines or created new cysteine codons, emphasizing the functional importance of these sites. These findings and the clinical features of Norrie disease suggested a possible role for the NDP gene in a neuroectodermal cell-cell interaction.
Familial Exudative Vitreoretinopathy
Shastry et al. (1997) reported 4 novel missense mutations in the NDP gene associated with 1 X-linked and 4 sporadic cases of familial exudative vitreoretinopathy (EVR2; 305390) (see 300658.0013).
Among 109 patients with pediatric vitreoretinopathies, Wu et al. (2007) identified 11 with a mutation in the NDP gene. They found that NDP mutations disrupting the cysteine-knot motif corresponded to severe retinal dysgenesis and a diagnosis of Norrie disease, whereas patients with noncysteine mutations had varying degrees of avascular peripheral retina, extraretinal vasculature, and subretinal exudate.
Kondo et al. (2007) screened 62 FEVR and 3 ND Japanese probands and family members for mutations in the NDP gene and identified 5 different mutations (1 splicing and 4 missense) in 4 FEVR patients and 2 ND patients. One proband with a missense mutation in the signal sequence of NDP had significant phenotypic heterogeneity between the affected eyes, indicating a diagnosis of FEVR or ND. Another proband, who had a splicing mutation, exhibited typical features of ND, whereas a maternal nephew was diagnosed with FEVR. In addition, 1 FEVR family with a missense mutation had affected female carriers: the 5-year-old proband's 42-year-old mother and a 13-year-old sister had milder-appearing FEVR, whereas 2 other carrier sisters exhibited only retinal vascular tortuosity. However, in another FEVR family with the same missense mutation, a 39-year-old female carrier had normal fundi bilaterally. Kondo et al. (2007) noted that although ND and FEVR are viewed as distinct diseases, the phenotypic spectrum of each is diverse, and they share multiple common features.
Using a norrin-based reporter assay to analyze the effects of FEVR-causing mutations, Qin et al. (2008) demonstrated that a nonsense mutation in FZD4 completely abolished signaling activity, whereas missense mutations in FZD4 and LRP5 caused a moderate level of reduction, and a double missense mutation in both genes caused a severe reduction in activity, correlating roughly with clinical phenotypes. Norrin mutants, however, showed variable effects on signal transduction, and no correlation with clinical phenotypes was observed; norrin mutants also showed impaired cell surface binding. Qin et al. (2008) concluded that norrin signaling is involved in FEVR pathogenesis, but suggested the presence of an unknown parallel pathway at the level of receptor/ligand binding as evidenced by the moderate and variable signal reduction lacking a clear genotype/phenotype correlation.
Berger et al. (1996) used gene targeting technology to generate Ndp mutant mice. Hemizygous mice carrying a replacement mutation in exon 2 of the Ndp gene developed retrolental structures in the vitreous body and showed an overall disorganization of the retinal ganglion cell layer. The outer plexiform layer disappeared occasionally, resulting in a juxtaposed inner and outer nuclear layer. The ocular findings were consistent with observations in patients with Norrie disease.
In a patient with Norrie disease (310600), Berger et al. (1992) identified a 685G-C transversion in exon 3 of the NDP gene, resulting in an arg90-to-pro (R90P) substitution. The patient had no hearing impairment or mental disturbances, but had a family history of the disorder.
In a patient with Norrie disease (310600), Berger et al. (1992) identified a 640C-G transversion in exon 3 of the NDP gene, resulting in a ser75-to-cys (S75C) substitution.
In a patient with Norrie disease (310600), Meindl et al. (1992) identified a 595T-A in the NDP gene, resulting in a val60-to-glu (V60E) substitution, inherited from the mother.
In a patient with Norrie disease (310600), Meindl et al. (1992) identified a 547A-G transition in the NDP gene, resulting in a tyr44-to-cys (Y44C) substitution.
In a patient with Norrie disease (310600), Meindl et al. (1992) identified a 703G-A transition in the NDP gene, resulting in a cys96-to-tyr (C96Y) substitution.
In a family with X-linked exudative vitreoretinopathy (EVR2; 305390) manifested by members of 4 generations (Dudgeon, 1979) and found to have possible linkage to markers in the region of the Norrie disease locus (Fullwood et al., 1993), Chen et al. (1993) demonstrated a C-to-T transition in the NDP gene, resulting in a leu124-to-phe (L124F) substitution in the highly conserved region of the NDP gene. The mutation was absent in unaffected family members and in normal controls.
In a family with a manifesting female carrier of Norrie disease (310600), Chen et al. (1993) identified a 614G-C transversion in the NDP gene, resulting in a cys69-to-ser (C69S) substitution. The carrier female had been noted to have severely impaired vision at age 2. Examination revealed a cataract in the right eye and total retinal detachment with a vascularized mass behind the lens. In the left eye, a retinal fold and traction retinal detachment in the temporal periphery were evident. The child was otherwise normal. Her carrier mother was normal. Two of the mother's brothers had Norrie disease.
In a patient with Norrie disease (310600), Wong et al. (1993) identified a dinucleotide GC-to-AA change in the NDP gene, resulting in a cys128-to-ter (C128X) substitution. The mutant protein lacked the last 6 amino acids of the carboxyl terminus. Wong et al. (1993) pointed out that the NDP protein normally has 11 cysteines, that the codon 128 mutation involved the tenth cysteine, and that most reported mutations have involved this amino acid residue.
In 2 Japanese males with Norrie disease (310600) from apparently unrelated families, Isashiki et al. (1995) identified an A-to-G transition at the initiation codon of exon 2 of the NDP gene, resulting in a met1-to-val (M1V) substitution. Both mothers were heterozygous for the mutation. Neither patient showed mental retardation or hearing impairment. Although the 2 families had lived in the same prefecture in southwestern Japan for at least 2 centuries, no relationship between the 2 families could be identified. All previously identified mutations had occurred in single families, indicating a marked heterogeneity of mutations. The finding of the same mutation in 2 apparently unrelated families, taken with the rarity of the disease, suggested that they shared a common ancestor.
In a 29-year-old male patient with X-linked exudative vitreoretinopathy (EVR2; 305390), Fuchs et al. (1995) found an arg121-to-trp (R121W) mutation in the NDP gene. Low visual acuity had been noted since birth. When the patient was 3 years old, the right eye was enucleated because an intraocular tumor was suspected. Histologic examination showed severe intraocular inflammation without malignancy. Visual acuity in the left eye remained unchanged until adulthood. The retina showed severe temporal dragging of the vessels, including the macula. Severely reduced visual acuity was known in several maternal male relatives; the mother and maternal grandmother had normal visual acuity.
Shastry et al. (1995) identified the same mutation in affected members in 3 generations of a family segregating X-linked exudative vitreoretinopathy.
Shastry (1998) identified the R121W mutation in a 'simplex' case of exudative vitreoretinopathy.
A different substitution at the same codon (R121L) has been described (300658.0017).
In affected members of a large Cuban kindred with Norrie disease (310600), Fuchs et al. (1994) identified a 454T-G transversion in the NDP gene, resulting in a leu13-to-arg (L13R) substitution. The nucleotide substitution creates a new HhaI restriction site. This mutation was identified in a large Cuban pedigree which consisted of 380 members, 46 of whom were affected. The disorder showed a typical pattern of X-linked inheritance over 7 generations. Eighteen patients examined shared similar clinical features. Pseudoglioma was always present in both eyes, frequently with phthisis bulbi, enophthalmos, opaque cornea, and cataract. In addition, about 45% of the patients showed moderate or severe mental retardation. Hearing loss was recognized in 78% of the patients, with different ages of onset.
Rehm et al. (1997) identified a large Costa Rican kindred in which 15 males were afflicted with congenital blindness, progressive hearing loss, and venous insufficiency. Because of an X-linked pattern of inheritance and the ophthalmologic and otologic findings, including bilateral retinal dysplasia and detachment and progressive bilateral sensorineural hearing loss, a tentative diagnosis of Norrie disease (310600) was considered. However, venous insufficiency was a clinical finding apparently not previously recognized in association with Norrie disease. Linkage analysis using microsatellite repeat markers demonstrated linkage to the Norrie disease region and studies of the NDP gene showed a point mutation in the third exon resulting in an leu61-to-phe (L61F) substitution. No obligate carrier females had any ocular or relevant pathology, but all affected males had varicose veins with peripheral venous stasis ulcers. Phlebography and other radiologic examinations showed deep venous system insufficiency and moderate dilatation of veins. Transfemoral arteriography showed patency of the femoral and distal arterial system.
Shastry et al. (1997) found an H42R mutation of the NDP gene segregating with exudative vitreoretinopathy (305390) in 3 generations of a family. They also identified mutations in the NDP gene in 4 sporadic cases of FEVR.
In a boy with Norrie disease (310600), Chynn et al. (1996) identified a 1-bp deletion in codon 35 of the NDP gene. The deletion changed the amino acids encoded by codons 35 through 39 and resulted in a premature stop at codon 40. The unaffected mother was heterozygous for the mutation.
In an Italian family in which 5 males in 4 generations had characteristic ophthalmologic findings of Norrie disease (310600), Torrente et al. (1997) identified an ala105-to-thr (A105T) missense mutation in the NDP gene. Affected individuals had no mental retardation or hearing abnormality.
In an Italian family with exudative vitreoretinopathy (EVR2; 305390) in an X-linked pedigree pattern, Torrente et al. (1997) demonstrated a cys110-to-gly (C110G) mutation in the NDP gene.
In a large kindred with X-linked recessive exudative vitreoretinopathy (EVR2; 305390), Johnson et al. (1996) identified an arg121-to-leu (R121L) mutation in the NDP gene. The clinical phenotype and rate of disease progression were extremely variable, with progression to total retinal detachment occurring before the age of 2 years in some and later than 21 years in others. Johnson et al. (1996) pointed out that all mutations identified in X-linked vitreoretinopathy have been missense mutations, presumably not affecting the 3-dimensional structure of the NDP gene product. Note that the same codon is involved in the arg121-to-trp mutation (300658.0010). Johnson et al. (1996) suggested that the mutations causing X-linked vitreoretinopathy cluster around residues 121-126, but this is not entirely true, as indicated by the cys110-to-gly mutation (300658.0016) and the his42-to-arg mutation (300658.0013).
Black et al. (1999) reported a woman with a unilateral variant of Coats disease (300216) who gave birth to a son affected by Norrie disease (310600). Both carried a 704C-G transversion in the NDP gene, resulting in a cys96-to-trp (C96W) substitution. Subsequent analysis of the retinas of 9 enucleated eyes from males with Coats disease demonstrated a somatic C96W mutation in the NDP gene in 1 that was not present in nonretinal tissue. Black et al. (1999) suggested that Coats telangiectasis is secondary to somatic mutation in the NDP gene, which results in a deficiency of norrin within the developing retina. This supported observations that the protein is critical for normal retinal vasculogenesis. The authors noted that a cys96-to-tyr substitution (300658.0005) had previously been described.
In a boy with Norrie disease (310600), Lev et al. (2007) identified a 134T-A transversion in the NDP gene, resulting in a val45-to-glu (V45E) substitution. He had profound mental retardation and myoclonic seizures with hypsarrhythmia on EEG. His asymptomatic mother was heterozygous for the mutation. Bioinformatic analysis indicated that V45E lies within an extracellular localization motif and may alter the distribution pattern of norrin, which in turn may alter norrin-mediated cell-cell communication.
In affected male members of a family with Norrie disease (310600), Walker et al. (1997) identified a 626C-A transversion in exon 3 of the NDP gene, resulting in a ser73-to-ter (S73X) substitution. Affected members had a severe ocular phenotype, but no mental retardation or deafness.
In affected male members of a family with Norrie disease (310600), Walker et al. (1997) identified a 710C-T transition in exon 3 of the NDP gene, resulting in a ser101-to-phe (S101F) substitution. Affected members had a less severe ocular phenotype compared to other patients with Norrie disease and no mental retardation or deafness.
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