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Berlin Brandenburg

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  • 1
    In: International Journal of Dermatology, August 2016, Vol.55(8), pp.898-902
    Description: Papillon–Lefèvre syndrome is an autosomal recessive genodermatosis typically manifesting with the constellation of palmoplantar keratoderma and progressive early‐onset periodontitis. The cutaneous phenotype can be strikingly psoriasiform, possibly posing a diagnostic challenge. This rare disorder is caused by loss‐of‐function mutations in the gene, which encodes cathepsin C. We report six patients with Papillon–Lefèvre syndrome from five consanguineous Turkish families, in whom genetic analysis of the gene revealed four recurrent mutations (c.415G〉A; c.1015C〉T; c.1019A〉G; and c.103–105del) and a novel missense mutation (c.117G〉T) in the homozygous state.
    Keywords: Genetic Carrier Screening ; Mutation, Missense ; Cathepsin C -- Genetics ; Papillon-Lefevre Disease -- Genetics;
    ISSN: 0011-9059
    E-ISSN: 1365-4632
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  • 2
    Language: English
    In: The American Journal of Human Genetics, 05 March 2015, Vol.96(3), pp.432-439
    Description: As a result of a whole-exome sequencing study, we report three mutant alleles in , a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C〉T (p.Gln205 ) and the missense mutations c.3044C〉T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A〉C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C〉T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the -deficient fish mutants (medaka) and (zebrafish).
    Keywords: Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 3
    Language: English
    In: The Journal of clinical investigation, September 2015, Vol.125(9), pp.3585-99
    Description: The genetic disorder Kabuki syndrome (KS) is characterized by developmental delay and congenital anomalies. Dominant mutations in the chromatin regulators lysine (K)-specific methyltransferase 2D (KMT2D) (also known as MLL2) and lysine (K)-specific demethylase 6A (KDM6A) underlie the majority of cases. Although the functions of these chromatin-modifying proteins have been studied extensively, the physiological systems regulated by them are largely unknown. Using whole-exome sequencing, we identified a mutation in RAP1A that was converted to homozygosity as the result of uniparental isodisomy (UPD) in a patient with KS and a de novo, dominant mutation in RAP1B in a second individual with a KS-like phenotype. We elucidated a genetic and functional interaction between the respective KS-associated genes and their products in zebrafish models and patient cell lines. Specifically, we determined that dysfunction of known KS genes and the genes identified in this study results in aberrant MEK/ERK signaling as well as disruption of F-actin polymerization and cell intercalation. Moreover, these phenotypes could be rescued in zebrafish models by rebalancing MEK/ERK signaling via administration of small molecule inhibitors of MEK. Taken together, our studies suggest that the KS pathophysiology overlaps with the RASopathies and provide a potential direction for treatment design.
    Keywords: Exome ; Mutation ; Abnormalities, Multiple -- Genetics ; Face -- Abnormalities ; Hematologic Diseases -- Genetics ; MAP Kinase Signaling System -- Genetics ; Monomeric Gtp-Binding Proteins -- Genetics ; Telomere-Binding Proteins -- Genetics ; Vestibular Diseases -- Genetics ; Zebrafish Proteins -- Genetics
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 4
    In: Human Molecular Genetics, 2017, Vol. 26(15), pp.2923-2932
    Description: CACNA1D encodes the pore-forming α 1 -subunit of Ca v 1.3, an L-type voltage-gated Ca 2+ -channel. Despite the recent discovery of two de novo missense gain-of-function mutations in Ca v 1.3 in two individuals with autism spectrum disorder (ASD) and intellectual disability CACNA1D has not been considered a prominent ASD-risk gene in large scale genetic analyses, since such studies primarily focus on likely-disruptive genetic variants. Here we report the discovery and characterization of a third de novo missense mutation in CACNA1D (V401L) in a patient with ASD and epilepsy. For the functional characterization we introduced mutation V401L into two major C-terminal long and short Ca v 1.3 splice variants, expressed wild-type or mutant channel complexes in tsA-201 cells and performed whole-cell patch-clamp recordings. Mutation V401L, localized within the channel’s activation gate, significantly enhanced current densities, shifted voltage dependence of activation and inactivation to more negative voltages and reduced channel inactivation in both Ca v 1.3 splice variants. Altogether, these gating changes are expected to result in enhanced Ca 2+ -influx through the channel, thus representing a strong gain-of-function phenotype. Additionally, we also found that mutant channels retained full sensitivity towards the clinically available Ca 2+ -channel blocker isradipine. Our findings strengthen the evidence for CACNA1D as a novel candidate autism risk gene and encourage experimental therapy with available channel-blockers for this mutation. The additional presence of seizures and neurological abnormalities in our patient define a novel phenotype partially overlapping with symptoms in two individuals with PASNA (congenital primary aldosteronism, seizures and neurological abnormalities) caused by similar Ca v 1.3 gain-of-function mutations.
    Keywords: Autism Spectrum Disorder -- Genetics ; Calcium Channels, L-Type -- Genetics;
    ISSN: 0964-6906
    E-ISSN: 1460-2083
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  • 5
    In: eLife, Vol.5
    Description: The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a , encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFκB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression. DOI: http://dx.doi.org/10.7554/eLife.14277.001 eLife digest Cancer can develop when cells in the body gain mutations that allow them to grow and divide rapidly. Some of these mutations may affect the activity of genes that usually act to prevent cancer from developing. Several such “tumor suppressor” genes have been identified, but it is likely that many remain undiscovered and it is far from fully understoodhow all these genes work. One way to identify new tumor suppressor genes is to examine tumors to search for genes that have gained mutations that block their activity, known as loss-of-function mutations. Hatzold et al. identified a new and rather unexpected tumor suppressor gene by studying a zebrafish mutant that develops skin cancer as the embryo grows. The experiments showed that cells in the skin of the developing embryos of this mutant grow excessively and start to invade deeper tissues in the body. This behavior is caused by loss-of-function mutations in a gene called atp1b1a . This gene encodes part of an ion pump protein that helps to control the amount of water and ions in cells and in body fluids. Further experiments showed that this tumor suppressor gene does not act in the skin cells themselves but in other cells of organs such as the kidney. The kidney is involved in controlling the water and ion content of the body (known as osmoregulation), and the atp1b1a mutants have lower levels of ions and increased levels of water than normal zebrafish. Cancer formation could be completely blocked when the mutant embryos were kept in a solution that had the same salt and water content as the animals, instead of regular fresh water. This suggests that exposure of cells to body fluids with decreased ion and increased salt contents, a condition also called hypotonic stress, increases the risk of developing some tumors. Osmoregulatory organs that are not working efficiently, or injuries that expose cells to different ion and water levels can both cause hypotonic stress. The next steps are to investigate whether this stress also promotes cancer formation in mammals, including humans. DOI: http://dx.doi.org/10.7554/eLife.14277.002
    Keywords: Cancer Biology ; Developmental Biology And Stem Cells ; Research Article ; Basal Cell Carcinogenesis ; Na/K-Atpase ; Epithelial Polarity ; Zebrafish
    E-ISSN: 2050-084X
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  • 6
    Language: English
    In: The American Journal of Human Genetics, 06 November 2014, Vol.95(5), pp.622-632
    Description: Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs 6), in , encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in are a major cause of Filippi syndrome.
    Keywords: Biology
    ISSN: 0002-9297
    E-ISSN: 1537-6605
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  • 7
    Language: English
    In: Human Genetics, 2013, Vol.132(11), pp.1311-1320
    Description: Otofaciocervical syndrome (OFCS) is an autosomal recessively inherited disorder characterized by facial dysmorphism, external ear anomalies with preauricular pits and hearing impairment, branchial cysts or fistulas, anomalies of the vertebrae and the shoulder girdle, and mild intellectual disability. In a large consanguineous family with OFCS from Turkey, we performed whole-exome sequencing (WES) of a single pooled DNA sample of four affected individuals. Filtering for variants with a percentage of alternate reads ≥90 % and a coverage of at least five reads identified only a single novel homozygous variant, c.497G〉T, located in PAX1 that co-segregated with the disease in the family. PAX1 encodes a transcription factor with a critical role in pattern formation during embryogenesis in vertebrates. The mutation is predicted to substitute the glycine at position 166 to valine (p.G166V) within the highly conserved paired-box domain of the PAX1 protein. We performed a dual luciferase reporter assay to examine the transactivation of a regulatory sequence in the Nkx3 - 2 promoter region, which is a direct target of mouse Pax1 transcriptional regulation. We observed a significantly reduced transactivation in HEK293T cells overexpressing Pax1 G157V in comparison to Pax1 WT expressing cells, indicating a reduced DNA-binding affinity of the mutant protein. Taken together, our results show that the strategy of pooling DNA is a powerful, cost-effective application for WES in consanguineous families and establish PAX1 as a new disease-causing gene for OFCS and as part of the EYA-DACH-SIX-PAX network, important in early embryogenesis.
    Keywords: Embryogenesis ; Cysts ; Immunogenetics;
    ISSN: 0340-6717
    E-ISSN: 1432-1203
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  • 8
    In: American Journal of Medical Genetics Part A, December 2016, Vol.170(12), pp.3282-3288
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.37931/abstract Byline: Nina Bogershausen, Umut Altunoglu, Filippo Beleggia, Gokhan Yigit, Hulya Kayserili, Peter Nurnberg, Yun Li, Janine Altmuller, Bernd Wollnik Kabuki syndrome (KS) is a rare developmental disorder characterized by multiple congenital malformations, postnatal growth retardation, intellectual disability, and recognizable facial features. It is mainly caused by mutations in either KMT2D or KDM6A. We describe a 14-year-old boy with KS presenting with an unusual combination of bilateral microphthalmia with orbital cystic venous lymphatic malformation and neonatal cholestasis with bile duct paucity, in addition to the typical clinical features of KS. We identified the novel KMT2D mutation c.10588delC, p.(Glu3530Serfs*128) by Mendeliome (Illumina TruSight One[R]) sequencing, a next generation sequencing panel targeting 4,813 genes linked to human genetic disease. We analyzed the Mendeliome data for additional mutations which might explain the exceptional clinical presentation of our patient but did not find any, leading us to suspect that the above named symptoms might be part of the KMT2D-associated spectrum of anomalies. We thus extend the range of KS-associated malformations and propose a hypothetical connection between KMT2D and Notch signaling. [c] 2016 Wiley Periodicals, Inc. Article Note: Nina Bogershausen and Umut Altunoglu contributed equally to this work. Conflicts of interest: None. Patient consent: Written informed consent for the genetic investigation and the publication of results and photographs were obtained from the patient's parents. Ethics approval: The ethical committee of the University Hospital Goettingen, Goettingen, Germany. Supporting information: Additional Supporting Information may be found in the online version of this article Additional supporting information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Table S1. Laboratory tests performed at two weeks of age Table S2. Genes associated with isolated and syndromic microphtalmia analyzed in the mendeliome dataset
    Keywords: Kabuki Syndrome ; Kmt2d ; Cyst ; Microphthalmia ; Venous Lymphatic Malformation ; Vascular Malformation ; Cholestasis ; Bile Duct Paucity ; Notch Signaling
    ISSN: 1552-4825
    E-ISSN: 1552-4833
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  • 9
    In: American Journal of Medical Genetics Part A, January 2017, Vol.173(1), pp.264-267
    Description: Byline: Shahida Moosa, Helena Bohrer-Rabel, Janine Altmuller, Filippo Beleggia, Peter Nurnberg, Yun Li, Gokhan Yigit, Bernd Wollnik Heterozygous germline mutations in MTOR have been shown to underlie Smith-Kingsmore syndrome, a rare autosomal dominant syndrome characterized by macrocephaly, developmental delay, and dysmorphic facial features. Recently, two unrelated families with the MTOR mutation, c.5395G〉A p.(Glu1799Lys), were reported. Here, we describe siblings from a non-consanguineous German family in whom we identified the same heterozygous missense mutation in MTOR. Remarkably, in all reported families with Smith-Kingsmore syndrome and the MTOR c.5395G〉A mutation, including the family described herein, healthy parents of recurrently affected children do not have detectable levels of the mutation in tested tissues, lending credence to gonadal mosaicism as the underlying mechanism. Furthermore, the glutamic acid at position 1799 was shown to present a recurrent somatic mutation site in several cancers, including colon cancer, pointing to a somatic mutational hotspot in MTOR. Importantly, we highlight the occurrence of multiple intestinal polyps in the older sibling. Further patients are required to establish definitively whether polyp formation forms part of the SKS clinical spectrum. [c] 2016 Wiley Periodicals, Inc. Article Note: Conflicts of interest: Authors declare no conflict of interest. Supporting information: Additional Supporting Information may be found in the online version of this article Additional supporting information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Figure S1. (A) Electropherograms showing heterozygous c.5395G〉A mutation in exon 39 of MTOR (NM_004958.3): present in both siblings, absent in both parents. (B) (upper panel) IGV "view as pairs" screenshot showing the heterozygous SNP rs2275527 (green) and the mutation c.5395G〉A (red) and (lower panel) Cross-species alignment showing conservation down to Danio rerio of the p.Glu1799 residue affected by the mutation (boxed in black). Table S1. Comparison of clinical features of patients with germline MTOR mutations.
    Keywords: Mtor ; Smith–Kingsmore Syndrome ; Macrocephaly ; P.Glu1799 Somatic Hotspot
    ISSN: 1552-4825
    E-ISSN: 1552-4833
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  • 10
    In: American Journal of Medical Genetics Part A, March 2016, Vol.170(3), pp.728-733
    Description: Byline: Gokhan Yigit, Dagmar Wieczorek, Nina Bogershausen, Filippo Beleggia, Claudia Moller-Hartmann, Janine Altmuller, Holger Thiele, Peter Nurnberg, Bernd Wollnik Using whole-exome sequencing, we identified a homozygous acceptor splice-site mutation in intron 6 of the KATNB1 gene in a patient from a consanguineous Turkish family who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, and dental abnormalities. cDNA analysis revealed complete loss of the natural acceptor splice-site resulting either in the usage of an alternative, exonic acceptor splice-site inducing a frame-shift and premature protein truncation or, to a minor extent, in complete skipping of exon 7. Both effects most likely lead to complete loss of KATNB1 function. Homozygous and compound heterozygous mutations in KATNB1 have very recently been described as a cause of microcephaly with brain malformations and seizures. We extend the KATNB1 associated phenotype by describing a syndrome characterized by primordial dwarfism, lissencephaly, polysyndactyly, and dental anomalies, which is caused by a homozygous truncating KATNB1 mutation. [c] 2015 Wiley Periodicals, Inc. Article Note: Conflict of interests: None. Authors' Contributors: GY and BW conceived and designed the experiments; DW and CMH undertook patient management, collection of samples, and delineation of the phenotype; GY and JA performed the experiments; GY, NB, FB, HT, and PN analyzed the data; GY and BW wrote the paper. Patient consent: Obtained. Ethics approval: The ethical committee of the University Hospital Cologne, Cologne, Germany.
    Keywords: Katnb1 ; Katanin ; Microcephalic Primordial Dwarfism ; Polydactyly ; Lissencephaly
    ISSN: 1552-4825
    E-ISSN: 1552-4833
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