Alternative titles; symbols
HGNC Approved Gene Symbol: EBP
SNOMEDCT: 398719004, 398958000;
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38) : X:48,521,808-48,528,716 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Chondrodysplasia punctata, X-linked dominant | 302960 | X-linked dominant | 3 |
| MEND syndrome | 300960 | X-linked recessive | 3 |
The EBP gene encodes an integral membrane protein located mainly in the endoplasmic reticulum that functions as a key enzyme in the final steps of the sterol biosynthesis pathway (summary by Hartill et al., 2014).
EBP was originally cloned as a delta-receptor binding target for the phenylalkylamine calcium-ion antagonist emopamil, an antiischemic drug in animal models of stroke (Hanner et al., 1995).
EBP was shown to bind a number of structurally diverse molecules, including the immunosuppressant SR31747A (Labit-Le Bouteiller et al., 1998) and the chemotherapeutic agent tamoxifen (Cho et al., 1998). EBP was shown to function as a delta(8)-delta(7) sterol isomerase by complementation of a yeast erg2 mutant (Silve et al., 1996).
High-throughput chemical screening approaches have identified small molecules that stimulate the formation of oligodendrocytes from oligodendrocyte progenitor cells and functionally enhance remyelination in vivo. Hubler et al. (2018) showed that a wide range of these promyelinating small molecules function not through their canonical targets but by directly inhibiting CYP51 (601637), TM7SF2 (603414), or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to oligodendrocyte progenitor cells in purified form whereas analogous sterols that lack this structural feature have no effect. Hubler et al. (2018) concluded that their results defined a unifying sterol-based mechanism of action for most known small molecule enhancers of oligodendrocyte formation.
Hanner et al. (1995) and Schindelhauer et al. (1996) mapped the EBP gene to Xp11.23-p11.22 by radiation hybrid and FISH analysis. Obviously an earlier assignment of CDPX2 to Xq28 was an error. Traupe et al. (1992) had claimed exclusion of Xp11 as the site of the mutation in X-linked dominant chondrodysplasia punctata (CDPX2; 302960); molecular studies in this family by Derry et al. (1999) demonstrated that Xp11 is, in fact, not excluded.
Derry et al. (1999) suggested that the loss of males in utero may be related to the presence of toxic sterol intermediates. The fact that mutations in the gene encoding 7-dehydrocholesterol reductase (DHCR7; 602858), the final enzyme of cholesterol biosynthesis, cause Smith-Lemli-Opitz syndrome (SLOS; 270400), suggests a direct involvement for abnormal cholesterol biosynthesis in some features of the Td/CDPX2 phenotype.
X-linked Dominant Chondrodysplasia Punctata 2
Derry et al. (1999) identified heterozygous mutations in the EBP gene (see, e.g., 300205.0001-300205.0002) in 7 of 8 female patients with X-linked dominant chondrodysplasia punctata-2 CDPX2 (302960). Of the 7, 5 mutations were predicted to be complete null alleles (4 nonsense single-base substitutions and 1 intragenic deletion producing a frameshift and truncated protein). An in-frame 3-bp deletion and 2 identical nonsense mutations (R63X) involved the same potential methylated CpG dinucleotide, which may represent a 'hotspot' for mutations. The single missense mutation R110Q, like Td, altered a conserved amino acid; it was positioned only 3 amino acids distal to the Td substitution in the same cytoplasmic domain of the isomerase protein. One of the families with CDPX2 investigated by Derry et al. (1999) had been reported by Traupe et al. (1992) and by Clayton et al. (1989); another family had been reported by Holmes et al. (1987).
Simultaneously and independently, Braverman et al. (1999) used SSCP analysis and sequencing of genomic DNA to find heterozygous EBP mutations in all 7 cases of CDPX2 studied. They confirmed the functional significance of 2 missense alleles by expressing them in a sterol-delta(8)-isomerase-deficient yeast strain.
Because of the clinical similarities between X-linked dominant chondrodysplasia punctata-2 and CHILD syndrome (308050), Grange et al. (2000) analyzed plasma sterols in a patient with typical CHILD syndrome. The levels of 8-dehydrocholesterol and 8(9)-cholestenol were increased in this patient to the same degree as in CDPX2 patients. The authors subsequently identified a nonsense mutation in exon 3 of the patient's 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase gene. The authors suggested that at least some cases of CHILD syndrome are caused by 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase deficiency and are allelic to CDPX2, although the almost exclusively unilateral distribution of abnormalities in CHILD syndrome versus the bilateral disease of CDPX2 remained to be explained. Konig et al. (2002) stated that the association of CHILD syndrome with mutation in the EBP gene by Grange et al. (2000) was erroneous and was in fact a case of CDPX2 with predominantly unilateral involvement. Konig et al. (2002) pointed out that an X-linked dominant disorder usually showing an asymmetric involvement such as CDPX2 may give rise by way of exception to extreme lateralization, whereas the CHILD syndrome usually shows extreme lateralization but may exceptionally manifest itself in almost symmetrically arranged skin lesions.
Has et al. (2000) analyzed the EBP gene in 7 independent families. They found 3 nonsense mutations and 2 frameshift mutations (1 deletion and 1 insertion). In 2 families, known mutations were identified. The authors found no mutations in a grandmother exhibiting minor disease symptoms (such as sectorial cataract) or in healthy parents with 2 affected girls. They hypothesized that these unrelated families may exemplify somatic and gonadal mosaicism.
Herman et al. (2002) searched for mutations in 26 females with suspected X-linked dominant chondrodysplasia punctata. Mutations in the EBP gene were identified in 22 of the 26 females studied, including 20 of the 22 patients who demonstrated an abnormal sterol profile. Thirteen of the mutations were novel. Affected females had typical skin manifestations and all but 1 had skeletal dysplasia. Herman et al. (2002) concluded that plasma sterol analysis was a highly specific and sensitive indicator of the presence of an EBP mutation in females with suspected CDPX2, including a clinically unaffected mother of a sporadic case. No clear genotype/phenotype correlations were ascertained, probably because phenotypic expression is influenced substantially by the pattern of X-inactivation in an affected female.
MEND Syndrome
Milunsky et al. (2003) described a hemizygous nonmosaic missense mutation in the EBP gene (L18P; 300205.0013) in a 2.5-year-old Caucasian male with developmental delay, hypotonia, seizures, and patchy hypopigmentation of the skin, consistent with MEND syndrome (MEND; 300960).
In 2 unrelated boys with MEND syndrome, Furtado et al. (2010) identified a hemizygous missense mutation in the EBP gene (W47C; 300205.0014). Functional studies of the variant were not performed, but both patients had increased levels of plasma 8(9)-cholestenol and 8-dehydrocholesterol, consistent with an enzymatic defect. The mutation was inherited from an unaffected mother in both cases.
'Tattered' (Td) is an X-linked, semidominant mouse mutation associated with prenatal male lethality. Heterozygous females are small and at 4 to 5 days of age develop patches of hyperkeratotic skin where no hair grows, resulting in a striping of the coat in adults. Craniofacial anomalies and twisted toes have also been observed in some affected females. The phenotype of Td is similar to that seen in heterozygous human females with X-linked dominant chondrodysplasia punctata (CDPX2; 302960), as well as in another X-linked, semidominant mouse mutation, 'bare patches' (Bpa). The Bpa gene (NSDHL; 300275) was identified by Liu et al. (1999), who showed that it encodes a protein with homology to 3-beta-hydroxysteroid dehydrogenases that functions in one of the later steps of cholesterol biosynthesis. CDPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and alopecia, cataracts, and skeletal abnormalities including short stature, rhizomelic shortening of the limbs, epiphyseal stippling, and craniofacial defects. Derry et al. (1999) identified the defect in Td mice as a single amino acid substitution in the delta(8)-delta(7) sterol isomerase known as emopamil-binding protein (Ebp) and also identified alterations in human EBP in 7 unrelated CDPX2 patients.
Of the genes mapped to a 0.9-cM interval in the proximal region of the mouse X chromosome, Ebp emerged as a candidate (Derry et al. (1999)) based on the hypothesis that mutations in the phenotypically similar mutants Td and Bpa may involve proteins that act in the same metabolic pathway, and the observation that Ebp functions as a sterol isomerase (Silve et al., 1996). Derry et al. (1999) found that all Td mice showed a single nucleotide substitution at position 454, a G-to-A transition resulting in an amino acid substitution of arginine for glycine at amino acid position 107. Kelley et al. (1999) demonstrated increased amounts of 8-dehydrocholesterol and cholest-8(9)-en-3-beta-ol in the plasma and tissues of 5 patients with CDPX2 or severe idiopathic CDP, consistent with a defect in delta(8)-delta(7) isomerase function. Quantitatively and qualitatively very similar sterol profiles were found in female mice with the Td mutation.
In a sporadic case of X-linked dominant chondrodysplasia punctata-2 (CDPX2; 302960) manifested by asymmetric rhizomelia, epiphyseal stippling, and hemivertebrae, as well as cataracts, Derry et al. (1999) found a 198G-A nucleotide change in the EBP gene predicted to cause a trp29-to-ter (W29X) change in the protein. The patient had collodion skin at birth; alopecia and coarse hair were later features. The patient also had Dandy-Walker malformation with ventriculomegaly.
In a familial case of chondrodysplasia punctata (CDPX2; 302960) and in a sporadic case of CDPX, Derry et al. (1999) found a 298C-T nucleotide change in the EBP gene predicted to cause an arg63-to-ter (R63X) alteration in the protein. The familial case had asymmetric short stature, scoliosis, epiphyseal stippling, bilateral cataract, erythroderma, and patchy alopecia. In the sporadic case, asymmetric rhizomelia, postaxial polydactyly, scoliosis, bilateral clubfeet, erythroderma, and patchy alopecia were present, as well as hearing loss. Cataract was present in the right eye.
In a familial case of CDPX2 in which the diagnosis was made when the patient, of Hispanic extraction, was 13 years of age, Braverman et al. (1999) found the same R63X mutation; they cited the nucleotide change as a 187C-T transition in exon 2 of the EBP gene.
In a female of European extraction with chondrodysplasia punctata (CDPX2; 302960) in whom the diagnosis was made at age 7 years, Braverman et al. (1999) identified a 238G-A transition in exon 2 of the EBP gene, predicted to cause a glu80-to-lys (E80K) amino acid substitution in the protein.
Aughton et al. (2003) described this mutation in mosaic state in a boy with clinical features of CDPX2 (including those presumed to arise in females secondary to the functional mosaicism of random X inactivation). Other causes of CDPX2 in males, such as 47,XXY karyotype and hypomorphic (leaky) mutation, were excluded.
In a case of familial chondrodysplasia punctata (CDPX2; 302960) with spontaneous abortion at the age of 30 weeks, Braverman et al. (1999) found a G-to-T transversion at the first nucleotide of intron 3 of the EBP gene.
In an isolated case of chondrodysplasia punctata (CDPX2; 302960), Has et al. (2000) found a 1-bp deletion of A at position 390 in exon 4 of the EBP gene, generating a frameshift and a premature termination signal at codon 137.
In an isolated case of chondrodysplasia punctata (CDPX2; 302960), Has et al. (2000) found a 1-bp insertion of A following base 586 in exon 5 of the EBP gene, generating a frameshift and a premature termination signal at codon 196.
Ikegawa et al. (2000) reported an isolated Japanese case with typical chondrodysplasia punctata (CDPX2; 302960) with a 497G-A nucleotide change in exon 4 of the EBP gene, predicted to cause a trp129-to-ter (W129X) alteration in the protein.
Ikegawa et al. (2000) reported an isolated Japanese case with typical chondrodysplasia punctata (CDPX2; 302960) with a 634C-T nucleotide change in exon 5 of the EBP gene, predicted to cause a gln175-to-ter (Q175X) alteration in the protein.
Ikegawa et al. (2000) reported an isolated Japanese case with typical chondrodysplasia punctata (CDPX2; 302960) with a 698G-A nucleotide change in exon 5 of the EBP gene, predicted to cause a trp196-to-ter (W196X) alteration in the protein.
Has et al. (2000) described a family in which 2 children with chondrodysplasia punctata (CDPX2; 302960) had an arg147-to-his (R147H) mutation of the EBP gene but showed differing severity of the disease. Shirahama et al. (2003) described a patient with the same mutation, caused by a 440G-A transition in exon 4, which was also found in her clinically unaffected mother. Expression analysis demonstrated that the mutant allele was predominantly expressed in the patient, while both alleles were expressed in her mother. Methylation analysis revealed that the wildtype allele was predominantly inactivated in the patient, while the mutated allele was predominantly inactivated in her mother. Thus, differences in expression of the mutated allele caused by skewed X-chromosome inactivation produced the diverse phenotypes within this family. Shirahama et al. (2003) noted that anticipation was a striking clinical feature of CDPX2 in the studies of Sutphen et al. (1995) and Traupe et al. (1992) and suggested that skewed methylation may have a role in this phenomenon.
Milunsky et al. (2003) described a hemizygous nonmosaic leu18-to-pro (L18P) mutation in exon 2 of the EBP gene in a 2.5-year-old Caucasian male with developmental delay, hypotonia, seizures, and patchy hypopigmentation of the skin (MEND; 300960). Although the patient had several typical findings of CDPX2 (302960), no skeletal asymmetry or chondrodysplasia punctata was noted on skeletal survey at 6 weeks and 13 months of age. The levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma and in cultured fibroblasts; this prompted molecular analysis of EBP, which revealed the L18P mutation. The patient's mother, who was adopted, also had the L18P mutation. She had normal stature, no asymmetry, no cataracts, and a patch of hyperpigmentation on her chest, best visualized on Woods lamp examination, characteristic of CDPX2. Happle (2003) and Ikegawa (2004) commented on the report of Milunsky et al. (2003); Happle (2003) considered this patient to have an entity distinct from CDPX2.
In 2 unrelated boys with MEND syndrome (MEND; 300960), Furtado et al. (2010) identified a hemizygous c.141G-T transversion in exon 2 of the EBP gene, resulting in a trp47-to-cys (W47C) substitution at a highly conserved residue in transmembrane domain-1. Functional studies of the variant were not performed, but both patients had increased plasma 8(9)-cholestenol and 8-dehydrocholesterol, consistent with an enzymatic defect. The mutation was inherited from an unaffected mother in both cases.
In a 7-year-old boy with an atypical form of X-linked dominant chondrodysplasia punctata-2 (CDPX2; 302960), Arnold et al. (2012) identified a de novo hemizygous c.33C-A transversion in the EBP gene, resulting in a tyr11-to-ter (Y11X) substitution. The karyotype of the patient was 46,XY, and Arnold et al. (2012) suggested that postzygotic mosaicism had occurred in this patient.
In affected members of a Mexican family with MEND syndrome (MEND; 300960), originally reported by Barboza-Cerda et al. (2013), Barboza-Cerda et al. (2014) identified a hemizygous c.224T-A transversion in the EBP gene, resulting in an ile75-to-asn (I75N) substitution at a highly conserved residue in transmembrane domain-2. The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. It was present in 2 affected males tested and in the unaffected mother; there was no evidence of mosaicism for the mutation in the affected males. Functional studies of the variant were not performed, but the mutation carriers had increased levels of plasma 8(9)-cholestenol and 8-dehydrocholesterol, consistent with an enzymatic defect. Barboza-Cerda et al. (2014) concluded that this was a hypomorphic mutation.
In 4 affected males from a family with MEND syndrome (MEND; 300960), Hartill et al. (2014) identified a hemizygous c.139T-C transition in the EBP gene, resulting in a trp47-to-arg (W47R) substitution at a highly conserved residue in the first transmembrane domain near the cytoplasmic surface of the endoplasmic reticulum membrane. The mutation was not found in the dbSNP database. Functional studies of the variant were not performed, but patients had increased 8-dehydrocholesterol and 8(9)-cholestenol. Hartill et al. (2014) postulated that the mutant protein is hypomorphic. The main features in this family included intellectual disability and behavioral difficulties.
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