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Dive into the research topics where Nadina Ortiz Brüchle is active.

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Featured researches published by Nadina Ortiz Brüchle.


American Journal of Human Genetics | 2008

Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia.

Carsten Bergmann; Manfred Fliegauf; Nadina Ortiz Brüchle; Valeska Frank; Heike Olbrich; J. Kirschner; Bernhard Schermer; Ingolf Schmedding; Andreas Kispert; Bettina Kränzlin; Gudrun Nürnberg; Christian Becker; Tiemo Grimm; Gundula Girschick; Sally Ann Lynch; Peter Kelehan; Jan Senderek; Thomas J. Neuhaus; Thomas Stallmach; Hanswalter Zentgraf; Peter Nürnberg; Norbert Gretz; Cecilia Lo; Soeren S. Lienkamp; Tobias Schäfer; Gerd Walz; Thomas Benzing; Klaus Zerres; Heymut Omran

Many genetic diseases have been linked to the dysfunction of primary cilia, which occur nearly ubiquitously in the body and act as solitary cellular mechanosensory organelles. The list of clinical manifestations and affected tissues in cilia-related disorders (ciliopathies) such as nephronophthisis is broad and has been attributed to the wide expression pattern of ciliary proteins. However, little is known about the molecular mechanisms leading to this dramatic diversity of phenotypes. We recently reported hypomorphic NPHP3 mutations in children and young adults with isolated nephronophthisis and associated hepatic fibrosis or tapetoretinal degeneration. Here, we chose a combinatorial approach in mice and humans to define the phenotypic spectrum of NPHP3/Nphp3 mutations and the role of the nephrocystin-3 protein. We demonstrate that the pcy mutation generates a hypomorphic Nphp3 allele that is responsible for the cystic kidney disease phenotype, whereas complete loss of Nphp3 function results in situs inversus, congenital heart defects, and embryonic lethality in mice. In humans, we show that NPHP3 mutations can cause a broad clinical spectrum of early embryonic patterning defects comprising situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulas, and a wide range of congenital anomalies of the kidney and urinary tract (CAKUT). On the functional level, we show that nephrocystin-3 directly interacts with inversin and can inhibit like inversin canonical Wnt signaling, whereas nephrocystin-3 deficiency leads in Xenopus laevis to typical planar cell polarity defects, suggesting a role in the control of canonical and noncanonical (planar cell polarity) Wnt signaling.


Journal of The American Society of Nephrology | 2011

Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney Disease

Carsten Bergmann; Jennifer von Bothmer; Nadina Ortiz Brüchle; Andreas Venghaus; Valeska Frank; Henry Fehrenbach; Tobias Hampel; Lars Pape; Annegret Buske; Jón Einar Jónsson; Nanette Sarioglu; Antónia Santos; Jose Carlos Ferreira; Jan U. Becker; Reinhold Cremer; Julia Hoefele; Marcus R. Benz; Lutz T. Weber; Reinhard Buettner; Klaus Zerres

Autosomal dominant polycystic kidney disease (ADPKD) is typically a late-onset disease caused by mutations in PKD1 or PKD2, but about 2% of patients with ADPKD show an early and severe phenotype that can be clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD). The high recurrence risk in pedigrees with early and severe PKD strongly suggests a common familial modifying background, but the mechanisms underlying the extensive phenotypic variability observed among affected family members remain unknown. Here, we describe severely affected patients with PKD who carry, in addition to their expected familial germ-line defect, additional mutations in PKD genes, including HNF-1β, which likely aggravate the phenotype. Our findings are consistent with a common pathogenesis and dosage theory for PKD and may propose a general concept for the modification of disease expression in other so-called monogenic disorders.


The New England Journal of Medicine | 2008

Perinatal Deaths in a Family with Autosomal Dominant Polycystic Kidney Disease and a PKD2 Mutation

Carsten Bergmann; Nadina Ortiz Brüchle; Valeska Frank; Helga Rehder; Klaus Zerres

The authors report on a four-generation family carrying a mutation in the gene for ADPKD2 (PKD2) with previously undetected polycystic kidney disease. In the present generation, however, perinatal ...


The Journal of Pediatrics | 2012

Molecular karyotyping as a relevant diagnostic tool in children with growth retardation with Silver-Russell features.

Sabrina Spengler; Matthias Begemann; Nadina Ortiz Brüchle; Michael Baudis; Bernd Denecke; Peter Michael Kroisel; Barbara Oehl-Jaschkowitz; Bernd Schulze; Gisela Raabe-Meyer; Christiane Spaich; Peter Blümel; Anna Jauch; Ute Moog; Klaus Zerres; Thomas Eggermann

OBJECTIVE To determine the contribution of submicroscopic chromosomal imbalances to the etiology of Silver-Russell syndrome (SRS) and SRS-like phenotypes. STUDY DESIGN We performed molecular karyotyping in 41 patients with SRS or SRS-like features without known chromosome 7 and 11 defects using the Affymetrix SNP Array 6.0 system (Affymetrix, High Wycombe, United Kingdom). RESULTS In 8 patients, pathogenic copy number variations with sizes ranging from 672 kb to 9.158 Mb were identified. The deletions in 1q21, 15q26, 17p13, and 22q11 were associated with known microdeletion syndromes with overlapping features with SRS. The duplications in 22q13 and Xq25q27 represent unique novel copy number variations but have an obvious influence on the phenotype. In 5 additional patients, the pathogenetic relevance of the detected variants remained unclear. CONCLUSION Pathogenic submicroscopic imbalances were detectable in a significant proportion of patients with short stature and features reminiscent of SRS. Therefore, molecular karyotyping should be implemented in routine diagnostics for growth-retarded patients with even slight dysmorphisms suggestive for SRS.


Clinical Genetics | 2017

NSD1 duplication in Silver-Russell syndrome (SRS): molecular karyotyping in patients with SRS features.

Jana Sachwitz; Robert Meyer; György Fekete; Stephanie Spranger; Aušra Matulevičienė; Vaidutis Kučinskas; Alexia Bach; Andrea Luczay; Nadina Ortiz Brüchle; Katja Eggermann; Klaus Zerres; Miriam Elbracht; Thomas Eggermann

Silver–Russell syndrome (SRS) is a growth retardation syndrome characterized by intrauterine and postnatal growth retardation, relative macrocephaly and protruding forehead, body asymmetry and feeding difficulties. Nearly 50% of cases show a hypomethylation in 11p15.5, in 10% maternal uniparental disomy of chromosome 7 is present. A significant number of patients with SRS features also exhibit chromosomal aberrations. We analyzed 43 individuals referred for SRS genetic testing by molecular karyotyping. Pathogenic variants could be detected in five of them, including a NSD1 duplication in 5q35 and a 14q32 microdeletion. NSD1 deletions are detectable in overgrowth disorders (Sotos syndrome and Beckwith–Wiedemann syndrome), whereas NSD1 duplications are associated with growth retardation. The 14q32 deletion is typically associated with Temple syndrome (TS14), but the identification of a patient in our cohort reflects the clinical overlap between TS14 and SRS. As determination of molecular subtypes is the basis for a directed counseling and therapy, the identification of pathogenic variants in >10% of the total cohort of patients referred for SRS testing and in >16% of characteristic individuals with the characteristic SRS phenotype confirms the need to apply molecular karyotyping in this cohort.


Neuromuscular Disorders | 2016

Distally pronounced infantile spinal muscular atrophy with severe axonal and demyelinating neuropathy associated with the S230L mutation of SMN1.

Sabine Rudnik-Schöneborn; Nina Barišić; Katja Eggermann; Nadina Ortiz Brüchle; Petra Grđan; Klaus Zerres

Two Croatian siblings with atypical clinical findings in the presence of SMN1 gene mutations are reported. The girl presented with delayed motor development and weakness in hands and feet in her first year of life. She never stood or walked and developed scoliosis and joint contractures during childhood. Her hands and feet were non-functional when last seen at age 14 years. Her 4-year-old brother was more severely affected and had a clinical picture resembling infantile spinal muscular atrophy (SMA) type 1. He also showed unusual distally pronounced weakness and facial weakness. Both patients had no sensory deficits but gave evidence of a mixed axonal and demyelinating neuropathy with pronounced slowing in the distal nerve segments. Unexpectedly, both siblings showed a compound heterozygous SMN1 mutation (heterozygous deletion and missense mutation c.689C > T; p.S230L), thus confirming infantile SMA. In addition, next generation sequencing of 52 genes for hereditary neuropathies revealed a heterozygous missense mutation c.505T > C; p.Y169H in the SH3TC2 gene that was transmitted by the healthy father. Our observations widen the phenotypic consequences of SMN1 gene mutations and support the notion to look for additional genetic factors which may modify the clinical picture in atypical cases.


Human Mutation | 2008

Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel‐Gruber syndrome

Valeska Frank; Anneke I. den Hollander; Nadina Ortiz Brüchle; Marijke N. Zonneveld; Gudrun Nürnberg; Christian Becker; Gabriele du Bois; Heide Kendziorra; Susanne Roosing; Jan Senderek; Peter Nürnberg; Frans P.M. Cremers; Klaus Zerres; Carsten Bergmann


Journal of Investigative Dermatology | 2008

RSPO4 Is the Major Gene in Autosomal-Recessive Anonychia and Mutations Cluster in the Furin-Like Cysteine-Rich Domains of the Wnt Signaling Ligand R-spondin 4

Nadina Ortiz Brüchle; Jorge Frank; Valeska Frank; Jan Senderek; Ahmet Akar; Erol Koç; Dimitris Rigopoulos; Maurice A.M. van Steensel; Klaus Zerres; Carsten Bergmann


Human Mutation | 2007

Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel‐Gruber syndrome

Valeska Frank; Nadina Ortiz Brüchle; Silke Mager; Susanna G. M. Frints; Axel Bohring; Gabriele du Bois; Irmgard Debatin; Heide Seidel; Jan Senderek; Nesrin Besbas; Unda Todt; Christian Kubisch; Tiemo Grimm; Fulya Teksen; Sevim Balci; Klaus Zerres; Carsten Bergmann


Archives of Gynecology and Obstetrics | 2017

Prenatal ultrasound, genotype, and outcome in a large cohort of prenatally affected patients with autosomal-recessive polycystic kidney disease and other hereditary cystic kidney diseases

Florian Erger; Nadina Ortiz Brüchle; U. Gembruch; Klaus Zerres

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