H Engel

Philipps-Universität Marburg, Marburg an der Lahn, Hesse, Germany

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Publications (13)53.99 Total impact

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    ABSTRACT: The CHILD syndrome (MIM 308050), an acronym for congenital hemidysplasia with ichthyosiform nevus and limb defects, is an X-linked dominant trait with lethality for male embryos. Recently, we elucidated the underlying gene defect by demonstrating point mutations in NSDHL (NAD[P]H steroid dehydrogenase-like protein) at Xq28 in 6 patients with classic CHILD syndrome. The most striking clinical feature is an inflammatory nevus that usually shows a unique lateralization with strict midline demarcation. Ipsilateral defects involve all skeletal structures and internal organs such as the brain, the lung, the heart, or the kidney. As an exception to this rule, in some cases the CHILD nevus may occur in a more or less bilateral distribution. In 1997 Fink-Puches et al described a case of CHILD nevus with an almost symmetric arrangement. To test the correctness of the diagnosis, we now examined blood lymphocytes of this patient by single-strand conformation analysis and genomic sequencing. We identified a novel missense mutation in NSDHL that potentially may impair protein function. We conclude that a diagnosis of CHILD syndrome can be based on clinical features such as the highly characteristic morphology of the CHILD nevus. A symmetric distribution of this nevus can exceptionally be seen in patients with CHILD syndrome, and this bilateral involvement should not mislead the clinician to any other diagnosis. Apparently, the effect of random X-inactivation is responsible for different patterns of cutaneous involvement in female carriers of NSDHL mutations.
    Journal of the American Academy of Dermatology 05/2002; 46(4):594-6. · 4.91 Impact Factor
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    ABSTRACT: The novel member of the claudin multigene family, paracellin-1/claudin-16, encoded by the gene PCLN1, is a renal tight junction protein that is involved in the paracellular transport of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in human PCLN1 are associated with familial hypomagnesemia with hypercalciuria and nephrocalcinosis, an autosomal recessive disease that is characterized by severe renal magnesium and calcium loss. The complete coding sequences of mouse and rat Pcln1 and the murine genomic structure are here presented. Full-length cDNAs are 939 and 1514 bp in length in mouse and rat, respectively, encoding a putative open-reading frame of 235 amino acids in both species with 99% identity. Exon-intron analysis of the human and mouse genes revealed a 100% homology of coding exon lengths and splice-site loci. By radiation hybrid mapping, the murine Pcln1 gene was assigned directly to marker D16Mit133 on mouse chromosome 16 (syntenic to a locus on human chromosome 3q27, which harbors the human PCLN1 gene). Mouse multiple-tissue Northern blot showed Pcln1 expression exclusively in the kidney. The expression profile along the nephron was analyzed by reverse transcriptase-PCR on microdissected nephron segments and immunohistochemistry of rat kidney. Paracellin-1 expression was restricted to distal tubular segments including the thick ascending limb of Henle's loop, the distal tubule, and the collecting duct. The identification and characterization of the rodent Pcln1 genes provide the basis for further studies of paracellin-1 function in suitable animal models.
    Journal of the American Society of Nephrology 01/2002; 12(12):2664-72. · 8.99 Impact Factor
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    ABSTRACT: TFIIIB, TFIIIC2, and PTF/SNAPC are heteromultimeric general transcription factors (GTFs) needed for expression of genes encoding small cytoplasmic (scRNAs) and small nuclear RNAs (snRNAs). Their activity is stimulated by viral oncogenes, such as SV40 large T antigen and Adenovirus E1A, and is repressed by specific transcription factors (STFs) acting as anti-oncogenes, such as p53 and pRb. GTFs role as final targets of critical signal transduction pathways, that control cell proliferation and differentiation, and their involvement in gene expression regulation suggest that the genes encoding them are potential proto-oncogenes or anti-oncogenes or may be otherwise involved in the pathogenesis of inherited genetic diseases. To test our hypothesis through the positional candidate gene approach, we have determined the physical localization in the human genome of the 11 genes, encoding the subunits of these GTFs, and of three genes for proteins associated with TFIIIB (GTF3BAPs). Our data, obtained by chromosomal in situ hybridization, radiation hybrids and somatic cell hybrids analysis, demonstrate that these genes are present in the human genome as single copy sequences and that some cluster to the same cytogenetic band, alone or in combination with class II GTFs. Intriguingly, some of them are localized within chromosomal regions where recurrent, cytogenetically detectable mutations are seen in specific neoplasias, such as neuroblastoma, uterine leyomioma, mucoepidermoid carcinoma of the salivary glands and hemangiopericytoma, or where mutations causing inherited genetic diseases map, such as Peutz-Jeghers syndrome. Their molecular function and genomic position make these GTF genes interesting candidates for causal involvement in oncogenesis or in the pathogenesis of inherited genetic diseases.
    Oncogene 09/2001; 20(35):4877-83. · 8.56 Impact Factor
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    ABSTRACT: We have identified several cDNAs for the human Kir5.1 subunit of inwardly rectifying K(+) channels. Alternative splicing of exon 3 and the usage of two alternative polyadenylation sites contribute to cDNA diversity. The hKir5.1 gene KCNJ16 is assigned to chromosomal region 17q23.1-24.2, and is separated by only 34 kb from the hKir2.1 gene (KCNJ2). In the brain, Kir5.1 mRNA is restricted to the evolutionary older parts of the hindbrain, midbrain and diencephalon and overlaps with Kir2.1 in the superior/inferior colliculus and the pontine region. In the kidney Kir5.1 and Kir2.1 are colocalized in the proximal tubule. When expressed in Xenopus oocytes, Kir5.1 is efficiently targeted to the cell surface and forms electrically silent channels together with Kir2.1, thus negatively controlling Kir2.1 channel activity in native cells.
    FEBS Letters 04/2001; 491(3):305-11. · 3.58 Impact Factor
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    ABSTRACT: There is an ongoing discussion whether Lisch corneal dystrophy (band-shaped and whorled microcystic dystrophy of the corneal epithelium) represents a disorder that is different from Meesmann corneal dystrophy. The purpose of this study was to evaluate at the molecular level if Lisch and Meesmann corneal dystrophies are genetically distinct. We examined at the slit lamp a total of 48 members of a family with an aggregation of Lisch corneal dystrophy. Genomic DNA was extracted from leukocytes of the peripheral blood of seven affected and six unaffected members of this family. Mutational hotspots in the cornea-specific keratin genes K3 and K12 were scanned for mutations by single-strand conformation analysis. To test for linkage to the keratin K3 or K12 loci or for X-chromosomal inheritance, six (K3) and four (K12) microsatellite markers each flanking the keratin loci as well as 22 microsatellite markers covering the X-chromosome were typed. Linkage was analyzed using the MLINK and FASTMAP procedures. A total of 19 trait carriers were identified in six generations of the family. No hereditary transmission from father to son was observed. Linkage was excluded for the keratin K3 and K12 genes. Furthermore, single-strand conformation analysis detected no mutations in these genes. Multipoint linkage analysis revealed linkage with a maximum likelihood of the odds (LOD) score of 2.93 at Xp22.3. Linkage was excluded for Xp22.2 to Xqter. Lisch corneal dystrophy is genetically different from Meesmann corneal dystrophy. Evidence was found for linkage of the gene for Lisch corneal dystrophy to Xp22.3.
    American Journal of Ophthalmology 11/2000; 130(4):461-8. · 3.63 Impact Factor
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    ABSTRACT: We report for the first time that CHILD syndrome (MIM 308050), an X-linked dominant, male-lethal trait characterized by an inflammatory nevus with striking lateralization and strict midline demarcation, as well as ipsilateral hypoplasia of the body is caused by mutations in the gene NSDHL located at Xq28 (NAD(P)H steroid dehydrogenase-like protein) encoding a 3beta-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway. SSCA and genomic sequence analysis of NSDHL identified in 6 patients with CHILD syndrome, including one boy as well as a mother and her daughter, mutations potentially impairing protein function. This phenotype is distinct from, but shares various clinical and biochemical findings with chondrodysplasia punctata (CDPX2, MIM 302960). CDPX2 is due to mutations affecting a delta8-delta7 sterol isomerase (EBP, emopamil binding protein, at Xp11.22-p11.23) that functions downstream of NSDHL in a later step of cholesterol biosynthesis. EBP was unaffected in the patients analyzed by us demonstrating that CHILD syndrome and CDPX2 are not caused by allelic mutations. Two mouse X-linked dominant male-lethal traits, bare patches (Bpa) and striated (Str) had previously been associated with mutations in Nsdhl. They provide animal models for the study of CHILD syndrome, a further human condition due to mutations in a gene of the cholesterol synthesis pathway.
    American Journal of Medical Genetics 03/2000; 90(4):339-46.
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    ABSTRACT: Human SL1 is a general transcription initiation factor (GTF) essential for RNA polymerase I to start rRNA synthesis at class I promoters. It is comprised of the TATA box-binding protein (TBP) and three TBP-associated factors (TAF(I)48, TAF(I)63 and TAF(I)110). We have determined that the human genes TAF1A, TAF1B and TAF1C, encoding these three TAF(I) polypeptides, are localized at lq42, 2p25 and 16q24, respectively. All three genes are present as single copies in the human genome and map to different chromosomes, as shown by somatic cell hybrid panel and radiation hybrid panel analysis and FISH. Two of these genes, TAF1C and TAF1B, are transcribed into multiple RNAs, as determined through Northern analysis of mRNA from various human organs and cell lines. If translated into different polypeptides, this could result in production of variant isoforms of SL1 with different activation potentials.
    Cytogenetics and cell genetics 02/2000; 89(1-2):133-6.
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    ABSTRACT: The cDNAs for human and murine Receptor Activity Modifying Proteins and for the associated murine Calcitonin Receptor Like Receptor were isolated. The human RAMP1 and RAMP3 genes possess two introns and human RAMP2 possesses three introns. Human RAMP1 was assigned to chromosome 2q36-->q37.1, RAMP2 to 17q12-->q21.1 and RAMP3 to 7p13-->p12. Mouse Ramp1 was assigned to chromosome 1 and Ramp2 and Ramp3 were assigned to chromosome 11.
    Cytogenetics and cell genetics 01/2000; 90(1-2):115-8.
  • Mammalian Genome 11/1999; 10(10):1030-1. · 2.42 Impact Factor
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    ABSTRACT: Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister–Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient’s GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA<SUB>1</SUB> and TA<SUB>2</SUB>) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.
    Human Molecular Genetics 10/1999; · 7.69 Impact Factor
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    ABSTRACT: Functional characterization of a gene often requires the discovery of the full spectrum of its associated phenotypes. Mutations in the human GLI3 gene have been identified in Greig cepalopolysyndactyly, Pallister-Hall syndrome (PHS), and postaxial polydactyly type-A (PAP-A). We studied the involvement of GLI3 in additional phenotypes of digital abnormalities in one family (UR003) with preaxial polydactyly type-IV (PPD-IV), three families (UR014, UR015, and UR016) with dominant PAP-A/B (with PPD-A and -B in the same family), and one family with PHS. Linkage analysis showed no recombination with GLI3-linked polymorphisms. Family UR003 had a 1-nt frameshift insertion, resulting in a truncated protein of 1,245 amino acids. A frameshift mutation due to a 1-nt deletion was found in family UR014, resulting in a truncated protein of 1,280 amino acids. Family UR015 had a nonsense mutation, R643X, and family UR016 had a missense mutation, G727R, in a highly conserved amino acid of domain 3. The patient with PHS had a nonsense mutation, E1147X. These results add two phenotypes to the phenotypic spectrum caused by GLI3 mutations: the combined PAP-A/B and PPD-IV. These mutations do not support the suggested association between the mutations in GLI3 and the resulting phenotypes. We propose that all phenotypes associated with GLI3 mutations be called "GLI3 morphopathies," since the phenotypic borders of the resulting syndromes are not well defined and there is no apparent genotype-phenotype correlation.
    The American Journal of Human Genetics 10/1999; 65(3):645-55. · 11.20 Impact Factor
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    ABSTRACT: By in situ chromosomal hybridization, and by somatic cell and radiation hybrid analysis, we have determined the genomic position of the human genes encoding four TAFII subunits of TFIID (TAFII150, TAFII105, TAFII68, TAFII18), the three subunits of TFIIA (TFIIA35 and TFIIA19, both encoded by the same gene, and TFIIA12), CDK8, and SURB7. All of these proteins are bona fide components of human class II holoenzymes as well as targets of signal transduction pathways that regulate genome expression. The genes encoding them are present in the human genome in a single copy and are localized at 8q23, 18q11.2, 17q11.1-11.2, 1p21, 14q31, 15q21-23, 13q12, and 12p12, respectively. We have mapped all of them to chromosomal regions where hereditary genetic diseases have been localized or which are involved in malignancies, which makes them potential candidates for a causal involvement in these phenotypes.
    Somatic Cell and Molecular Genetics 06/1999; 25(3):185-9.
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    ABSTRACT: The novel weakly inward rectifying potassium channel Kir7.1 is a low-conductance channel that is predominantly expressed in epithelial cells. Here we describe a partial genomic characterization and the chromosomal assignment of the human Kir7.1 gene (KCNJ13). Analysis of the genomic structure using a PCR-based approach revealed a single 2088-bp intron in the coding region ofKCNJ13. PCR analysis of monochromosomal and radiation hybrid panels assignsKCNJ13to band 2q37 between markers D2S331 and D2S345. In addition, a single nucleotide polymorphism (C524→T), leading to an exchange of a Thr with an Ile residue at amino acid position 175, was found.
    Genomics 01/1999; · 3.01 Impact Factor