Wolfram Heinritz

Transcriptional regulator PRDM12 is essential for human pain perception

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype.

Mowat–Wilson syndrome (MWS) is a rare mental retardation—multiple congenital anomalies syndrome associated with typical facial dysmorphism. Patients can show a variety of other anomalies like short stature, microcephaly, Hirschsprung disease, malformations of the brain, seizures, congenital heart defects and urogenital anomalies. Mutations leading to haploinsufficiency of the ZFHX1B gene have been described as the underlying cause of this condition. We report on the clinical findings in a 2½‐year‐old boy with some aspects out of the MWS‐spectrum in addition to unusual anomalies and a novel missense mutation in the ZFHX1B gene.

New Mutations of EXT1 and EXT2 Genes in German Patients with Multiple Osteochondromas

Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects – usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2.

Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein

BackgroundAutosomal dominant Holt-Oram syndrome (HOS) is caused by mutations in the TBX5 gene and is characterized by congenital heart and preaxial radial ray upper limb defects. Most of the TBX5 mutations found in patients with HOS cause premature truncation of the primary TBX5 transcript. TBX5 missense mutations alter the three-dimensional structure of the protein and result in failed nuclear localization or reduced binding to target DNA. In this study we present our functional analyses of the novel and unusual c.1333delC mutation found in a patient with classical HOS.MethodsThe functional impact of this novel mutation was assessed by investigating the intracellular localization of the resulting TBX5 protein and its ability to activate the expression of its downstream target ANF.ResultsThe deletion of the cytosine is the first TBX5 frameshift mutation predicted to result in an elongated TBX5 protein with 74 miscoding amino acids and 62 supernumerary C-terminal amino acids. The c.1333delC mutation affects neither the nuclear localization, nor its colocalization with SALL4, but severely affects the activation of the ANF promoter.ConclusionThe mutation c.1333delC does not locate within functional domains, but impairs the activation of the downstream target. This suggests that misfolding of the protein prevents its biological function.

Pulmonary artery sling and congenital tracheal stenosis in another patient with Mowat–Wilson syndrome

Sibylle Strenge,* Wolfram Heinritz, Christiane Zweier, Anita Rauch, Udo Rolle, Andreas Merkenschlager, and Ursula G. Froster Medical Faculty, Institute of Human Genetics, University of Leipzig, Leipzig, Germany Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

Evidence for a Founder Effect of the Germline Fumarate Hydratase Gene Mutation R58P causing Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

We report on the results of clinical investigation, pedigree analysis, mutation screening and haplotyping in a family with the syndrome of multiple cutaneous and uterine leiomyomas (MCUL1) and a germline missense mutation (R58P) in the fumarate hydratase gene (FH). We provide evidence for a founder effect for the identified mutation and distant relationship of our family to another familial case of MCUL1 associated with renal cell cancer, which was recently published with the same mutation.

Multiple trichoepitheliomas: a novel mutation in the CYLD gene

Background  Trichoepitheliomas are benign neoplasms with follicular differentiation. They may present as a solitary lesion or as multiple lesions. Multiple trichoepitheliomas are inherited in an autosomal dominant pattern within families, with both variable penetrance and expressivity. Recent investigations support that mutations in CYLD, the gene affected in familial cylindromatosis as well as in Brooke–Spiegler syndrome, are also responsible for multiple trichoepitheliomas.

TGFBI (BIGH3) gene mutations in German families: two novel mutations associated with unique clinical and histopathological findings

Background: To report the clinical, histopathological and immunohistochemical findings of two novel mutations within the TGFBI gene. Methods: The genotype of 41 affected members of 16 families and nine sporadic cases was investigated by direct sequencing of the TGFBI gene. Clinical, histological and immunohistochemical characteristics of corneal opacification were reported and compared with the coding region changes in the TGFBI gene. Results: A novel mutation Leu509Pro was detected in one family with a geographic pattern-like clinical phenotype. Histopathologically we found amyloid together with non-amyloid deposits and immunohistochemical staining of Keratoepithelin (KE) KE2 and KE15 antibodies. In two families and one sporadic case the novel mutation Gly623Arg with a late-onset, map-like corneal dystrophy was identified. Here amyloid and immunohistochemical staining of only KE2 antibodies occurred. Further, five already known mutations are reported: Arg124Cys Arg555Trp Arg124His His626Arg, Ala546Asp in 13 families and five sporadic cases of German origin. The underlying gene defect within the TBFBI gene was not identified in any of the four probands with Thiel–Behnke corneal dystrophy. Conclusions: The two novel mutations within the TGFBI gene add another two phenotypes with atypical immunohistochemical and histopathological features to those so far reported.

A new mutation in the GJB3 gene in a patient with erythrokeratodermia variabilis

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Vascular parkinsonism in a CADASIL case with an intact nigrostriatal dopaminergic system

5 % of cerebral small vessel diseases manifesting mostly between the age of 40 and 60 years irrespective of vascular risk factors [1]. The clinical spectrum includes migraine, recurrent subcortical strokes, cognitive decline, and psychiatric manifestations [1, 2]. Here, we report for the first time a case of vascular parkinsonism and dementia showing functional integrity of the nigrostriatal dopaminergic system diagnosed as CADASIL by skin biopsy. A 55-year old male presented to our department with a two year history of reduced mobility, cognitive decline, chronic fatigue, and urinary incontinence. Previous diagnosis included major depression, however, the antidepressant therapy with mirtazapin was ineffective. Amisulpride had been administered due to hypochondric delusions. Hypertension and atrial fibrillation were treated adequately with metoprolol, digitoxin, and phenprocoumon, otherwise his LETTER TO THE EDITORS