Alternative titles; symbols
HGNC Approved Gene Symbol: RBP4
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38): 10:93,591,694-93,601,744 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.33 | Microphthalmia, isolated, with coloboma 10 | 616428 | Autosomal dominant | 3 |
| Retinal dystrophy, iris coloboma, and comedogenic acne syndrome | 615147 | Autosomal recessive | 3 |
Retinol-binding protein (RBP) is a monomeric-binding protein of 21 kD that specifically transports retinol, the alcoholic form of vitamin A, in plasma from its main store site, the liver, to target cells. RBP circulates almost entirely bound to thyroxine-binding transthyretin (TTR; 176300) (summary by Folli et al., 2005).
Rask et al. (1987) reported the complete amino acid sequence of serum retinol-binding protein. Pervaiz and Brew (1985) found homology of human serum RBP to bovine beta-lactoglobulin and to protein HCP.
Isken et al. (2008) cloned zebrafish rbp4, which encodes a predicted protein that shares significant identity with its mouse and human orthologs. In situ hybridization showed that zebrafish rbp4 was expressed in the yolk syncytial layer, starting with segmentation stages and persisting as development proceeded.
Using a cDNA probe for RBP4, Rocchi et al. (1989) performed in situ hybridization and Southern blot analysis of genomic DNA from somatic cell hybrids to map the RBP4 gene to 10q23-q24. Gray et al. (1995) found that the RBP4 gene resides just centromeric of the cluster of CYP2C genes (124020) on 10q24. By the study of recombinant inbred strains, Chainani et al. (1991) showed that the mouse Rbp4 locus is closely linked and just proximal to the locus for phenobarbital-inducible cytochrome P450-2c (Cyp-2c) at the distal end of chromosome 19.
Retinal Dystrophy, Iris Coloboma, and Comedogenic Acne Syndrome
In 2 German sisters with night blindness and retinal dystrophy who had no detectable serum RBP, retinol levels less than 20% of normal, and normal retinyl esters (RDCCAS; 615147), Seeliger et al. (1999) identified compound heterozygosity for missense mutations in the RBP4 gene (180250.0001 and 180250.0002). Both sisters also displayed severe comedogenic acne and widespread follicular keratosis.
Using exome capture and next-generation sequencing in a brother and sister with early-onset progressive severe retinal dystrophy, who were born of second-cousin parents, Cukras et al. (2012) identified homozygosity for a splice site mutation in the RBP4 gene (180250.0003). Lack of other classic symptoms of vitamin A deficiency in these patients suggested that some dietary vitamin A was being delivered to organs independently of RBP4, but that RBP4 was required to deliver sufficient levels of vitamin A to prevent retinal degeneration. Additional features included iris coloboma in the brother and persistent acne into the sixth decade of life in the sister.
Microphthalmia/Coloboma 10
In a 7-generation family segregating autosomal dominant microphthalmia or clinical anophthalmia and/or coloboma (MCOPCB10; 616428) mapping to chromosome 10q23, Chou et al. (2015) analyzed 3 genes in the critical region that have roles in vitamin A transport and identified a heterozygous missense mutation in the RBP4 gene (A75T; 180250.0004) in affected individuals and obligate carriers. Screening of DNA samples from 75 unrelated microphthalmia/coloboma cases revealed another missense mutation (A73T; 180250.0005) in 2 patients. Functional analysis demonstrated that both mutant retinol-binding proteins (RBPs) bind the STRA6 (610745) receptor with much higher affinity than wildtype yet carry little or no vitamin A. Consistent with these findings, all 3 A75T heterozygous carriers who were tested had fasting serum vitamin A levels below normal limits, and plasma retinol fluorescence was also reduced. Maternal penetrance was significantly greater than paternal penetrance (0.7 vs 0.1). Chou et al. (2015) therefore suggested that when the RBP4 mutation is maternally transmitted, there is decreased vitamin A delivery both at the placenta, involving maternal-derived RBP, and later at the developing eye primordia, involving fetal-derived RBP.
Associations Pending Confirmation
Increased levels of RBP4 in serum are associated with insulin resistance. Munkhtulga et al. (2007) identified a single-nucleotide polymorphism (SNP) in the 5-prime flanking region of the RBP4 gene, -803G-A (rs3758539) that showed association with susceptibility to type 2 diabetes (see 125853) in a case-control study of 281 diabetic Mongolian subjects and 511 controls (p = 0.0054). The -803A allele induced almost 2-fold greater transcriptional activity than the -803G allele, and was associated with higher binding affinity of hepatocyte nuclear factor 1-alpha (HNF1A; 142410) to its motif, located 5 bp upstream of the -803G-A SNP in the RBP4 enhancer region. The -803G-A SNP was also associated with increased serum RBP4 levels in diabetic patients. The chromosomal region of RBP4, 10q, had been linked to an increased risk for type 2 diabetes in Caucasians (Meigs et al., 2002) and Mexican Americans (Duggirala et al., 1999). Polymorphism in the TCF7L2 gene (602228), also located in the 10q region implicated in diabetes susceptibility, has been associated with susceptibility as well.
Quadro et al. (2002) stated that Rbp-null mice are unable to mobilize stored retinol from liver and develop impaired retinal function during the first month of life. Quadro et al. (2002) found that human RBP expressed from muscle, an ectopic source, suppressed the visual phenotype in Rbp-null mice. No human RBP was found in the retinal pigment epithelium of the transgenic mice, indicating that retinol uptake by the eye does not entail endocytosis of the carrier RBP.
Using DNA arrays, Yang et al. (2005) showed that expression of Rbp4 is elevated in adipose tissue of adipose-Glut4 (138190)-null mice. Yang et al. (2005) showed that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity (601665) and type 2 diabetes (125853). RBP4 levels were normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice caused insulin resistance. Conversely, genetic deletion of Rbp4 enhanced insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalized serum Rbp4 levels and improved insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum Rbp4 induced hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impaired insulin signaling in muscle. Thus, Yang et al. (2005) concluded that RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes.
Isken et al. (2008) found that reducing rbp4 levels in stra6 (610745)-deficient zebrafish embryos, a model of Matthew-Wood syndrome (MCOPS9; 601186), led to diminished mobilization of yolk vitamin A, alleviated embryonic defects, and reduced high fatality. The authors concluded that rbp4 disrupts vitamin A uptake homeostasis in stra6-deficient zebrafish.
In 2 German sisters with night blindness and retinal dystrophy who had no detectable serum RBP, retinol levels less than 20% of normal, and normal retinyl esters (RDCCAS; 615147), Seeliger et al. (1999) identified compound heterozygosity for an ile41-to-asn (I41N) substitution and a gly75-to-asp (G75D; 180250.0002) substitution in the RBP4 gene, both at conserved residues. Their unaffected mother, who had a low-normal retinol level and a plasma RBP level that was approximately 50% of normal, was heterozygous for the I41N mutation, as was an unaffected sister; neither mutation was found in their unaffected brother or in 100 controls. Both sisters also had inferior iris coloboma and both displayed severe comedogenic acne and widespread follicular keratosis.
Folli et al. (2005) demonstrated that although recombinant human N41 and D75 (180250.0002) RBPs form complexes with retinol and transthyretin (176300) in vitro, the mutant retinol-RBP complexes are significantly less stable than normal holo-RBP, as indicated by markedly facilitated release of retinol to phospholipid membranes by mutant RBP. The authors concluded that this altered interaction of retinol with RBP can result in the lowering of plasma retinol and RBP levels.
For discussion of the gly75-to-asp (G75D) mutation in the RBP4 gene that was found in compound heterozygous state in patients with retinal dystrophy, iris coloboma, and comedogenic acne syndrome (RDCCAS; 615147) by Seeliger et al. (1999), see 180250.0001.
In a Caucasian brother and sister with severe retinal dystrophy (615147), born of second-cousin parents, Cukras et al. (2012) identified homozygosity for a G-A transition in intron 2 (111+1G-A) of the RBP4 gene, predicted to disrupt the donor splice site. Their unaffected parents and an unaffected sib, as well as the unaffected grandparents from the family common relationship, were each heterozygous for the mutation, which was not found in 100 ethnically matched controls. Western blot analysis showed absence of wildtype RBP4 protein from the serum of the 2 affected sibs; in addition, serum retinol was undetectable. Additional features in the 63-year-old brother included small cornea, nuclear sclerotic cataract, inferiorly displaced pupil, and inferior iris coloboma extending into the retina and choroid, as well as patent ductus arteriosus that was repaired at 46 years of age; his 55-year-old sister had persistent acne into her sixth decade of life.
In affected members of a 7-generation family segregating autosomal dominant microphthalmia or clinical anophthalmia and/or coloboma (MCOPCB10; 616428), Chou et al. (2015) identified heterozygosity for a c.223G-A transition in exon 3 of the RBP4 gene, resulting in an ala75-to-thr (A75T) substitution at a highly conserved residue that corresponds to A57T in the mature polypeptide. The mutation, which segregated with disease in the family, was not found in more than 11,330 control chromosomes. Functional analysis demonstrated a dramatic reduction in retinol binding with A57T RBP compared to wildtype RBP; in addition, A57T RBP has 30- to 40-fold greater affinity for the STRA6 (610745) receptor than wildtype.
In 4 affected individuals from 2 unrelated families with microphthalmia or clinical anophthalmia and/or coloboma (MCOPCB10; 616428), Chou et al. (2015) identified heterozygosity for a c.217G-A transition in exon 3 of the RBP4 gene, resulting in an ala73-to-thr (A73T) substitution at a highly conserved residue that corresponds to A55T in the mature polypeptide. The mutation, which segregated with disease in both families, was not found in more than 11,330 control chromosomes; it occurred on a distinct haplotype in each family, indicating recurrence of the mutation. Functional analysis demonstrated a dramatic reduction in retinol binding with A55T RBP compared to wildtype RBP; in addition, A55T RBP has 30- to 40-fold greater affinity for the STRA6 (610745) receptor than wildtype. In the first family, the male proband and his male first cousin once removed had bilateral severe microphthalmia or clinical anophthalmia as well as developmental delay and seizures; in the second family, a mother had unilateral optic pit, whereas her daughter had left-sided microphthalmia and ventronasal iris coloboma.
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