A novel X‐linked multiple congenital anomaly syndrome associated with an EBP mutation

Abstract

Mutations of the gene coding for emopamil binding protein (EBP) can lead to deficient activity of 3-β-hydroxysteroid Δ(8), Δ(7) isomerase and are most commonly identified in. association with the X-linked dominant (male lethal) chondrodysplasia punctata (CDPX2), also known as Conradi-Hunermann syndrome. Our group has identified a hemizygous EBP mutation in males with a phenotype remarkable for Dandy-Walker malformation, cataracts, collodion skin and cryptorchidism. Additional findings of hydrocephalus, dysplasia of the corpus callosum, cardiovascular, craniofacial and skeletal anomalies were regularly seen in affected males and the family histories were supportive of an X-linked -recessive condition. The regularly reproducible constellation of cardinal features aligns very nicely with other disorders of sterol biosynthesis and is further distinguished by an absence of arty clinical manifestations in obligate carrier females. Biochemical analysis of blood from cases demonstrated markedly increased levels of 8(9)-cholestenol, and 8-dehydroeholesterol and a mildly increased level of 7-dehydrocholesterol; a similar pattern to what is seen in CDPX2. Sequence analysis of EJJP revealed a novel hemizygous missense mutation at position 141, predictive of a tryptophan to cysteine substitution (c.141G>T, p.W47C). The unaffected mothers were heterozygous for the c.141G>T mutation arid showed random X-inactivation pattern upon.

A novel X‐linked phenotype caused by hypomorphic EBP mutations

“…Subsequently, as noted by Furtado et al [2010], four affected male individuals with characteristic cerebral defects such as DandyWalker malformation and hypoplasia or absence of corpus callosum were described by Kelley et al [2005]. These authors did not provide molecular data but supported the proposed etiological concept of hypomorphic EBP mutations.…”

“…I read with great interest the excellent report on ''a novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation'' by Furtado et al [2010]. Admittedly, this phenotype is very unusual.…”

“…The impressive report of Furtado et al [2010] now describes, in a comprehensive way, the clinical spectrum of the new syndrome. In particular, the authors present a detailed overview of the neurological, skeletal, and cutaneous abnormalities as found in this trait, and they document a five-generation pedigree confirming the X-linked recessive mode of transmission of this distinct phenotype.…”

Pharmacological Targeting of the Epidermal Barrier

“…STS disease-causing variants contribute to the development of Xlinked ichthyosis [28]. EBP mutations are linked with Conradi-Hünermann-Happle or MEND syndromes [29,54]. MBTPS2 mutations can lead to the development of ichthyosis follicularisalopecia-photophobia syndrome, keratosis follicularis spinulosa decalvans and Olmsted syndrome, characterized by mutilating palmoplantar keratoderma with periorificial keratotic plaques [30].…”

Detergent Screening for NMR-Based Structural Study of the Integral Membrane Protein, Emopamil Binding Protein (Human Sterol Δ8-Δ7 Isomerase)

“…Representatively, a variety of different mutations of Δ7-sterol reductase cause a frequent malformation syndrome (Smith-Lemli-Opitz syndrome), and dysfunction of Δ8-Δ7 isomerase causes a Conradi-Hunermann-Happle (CHH) syndrome or male EBP disorder with neurological defects (MEND) syndrome. [7][8][9] The human Δ8-Δ7 sterol isomerase, which can bind to the antiischemic drug emopamil, was named emopamil binding protein (EBP). [10][11][12] In addition, as a variety of structurally distinct pharmacological compounds including receptor σ-ligand SR31747A, trifuoperazine, and tamoxifen showed an ability to inhibit the Δ8-Δ7 isomerase activity, it is needed to get structural information underlying the advanced mechanism of those inhibitors.…”