Gerhard Hammersen

Bio: Gerhard Hammersen is an academic researcher. The author has contributed to research in topics: Microcephaly & Disease gene identification. The author has an hindex of 4, co-authored 4 publications receiving 630 citations.

Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation

Abstract: We observed two unrelated consanguineous families with malformation syndromes sharing anophthalmia and distinct eyebrows as common signs, but differing for alveolar capillary dysplasia or complex congenital heart defect in one and diaphragmatic hernia in the other family. Homozygosity mapping revealed linkage to a common locus on chromosome 15, and pathogenic homozygous mutations were identified in STRA6, a member of a large group of "stimulated by retinoic acid" genes encoding novel transmembrane proteins, transcription factors, and secreted signaling molecules or proteins of largely unknown function. Subsequently, homozygous STRA6 mutations were also demonstrated in 3 of 13 patients chosen on the basis of significant phenotypic overlap to the original cases. While a homozygous deletion generating a premature stop codon (p.G50AfsX22) led to absence of the immunoreactive protein in patient's fibroblast culture, structural analysis of three missense mutations (P90L, P293L, and T321P) suggested significant effects on the geometry of the loops connecting the transmembrane helices of STRA6. Two further variations in the C-terminus (T644M and R655C) alter specific functional sites, an SH2-binding motif and a phosphorylation site, respectively. STRA6 mutations thus define a pleiotropic malformation syndrome representing the first human phenotype associated with mutations in a gene from the "STRA" group.

tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia.

Abstract: Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.

A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy.

Abstract: The following study describes the discovery of a new inherited metabolic disorder, dolichol kinase (DK1) deficiency. DK1 is responsible for the final step of the de novo biosynthesis of dolichol phosphate. Dolichol phosphate is involved in several glycosylation reactions, such as N-glycosylation, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and C- and O-mannosylation. We identified four patients who were homozygous for one of two mutations (c.295T→A [99Cys→Ser] or c.1322A→C [441Tyr→Ser]) in the corresponding hDK1 gene. The residual activity of mutant DK1 was 2%–4% when compared with control cells. The mutated alleles failed to complement the temperature-sensitive phenotype of DK1-deficient yeast cells, whereas the wild-type allele restored the normal growth phenotype. Affected patients present with a very severe clinical phenotype, with death in early infancy. Two of the patients died from dilative cardiomyopathy.

Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin-4 gene mutation.

Abstract: Cutis laxa is characterised by redundant, inelastic skin with deep wrinkling and additional variable systemic involvement. Mutations in fibulin-4 (EFEMP2) and fibulin-5 (FBLN5) were described to be causative for autosomal recessive cutis laxa type 1 in a few families each. The female patient was born to healthy consanguineous parents. Pregnancy was remarkable for fetal overgrowth and oligohydramnios. The newborn girl showed extreme bradycardia and died perinatally. Apart from overgrowth, cutis laxa, arachnodactyly of hands and feet with contractures of the third to fifth finger, medial rotation of feet, spina bifida of the os sacrum, microcephaly and facial dysmorphism were noted. Autopsy showed collapsed lungs with hypoplastic diaphragm and signs of cervical soft tissue bleedings due to fragility of vessels. Histologic examination showed fragmentation of elastic fibres with formation of cystic cavities in the medial layer of the aorta and central lung vessels. Sequencing of the elastin, fibulin-4 and fibulin-5 genes revealed a homozygous missense mutation (p.Cys267Tyr) in the fibulin-4 gene in the patient. Our observation increases the number of cases with fibulin-4 mutations to three and extends the phenotypic spectrum of fibulin-4 mutations by microcephaly, overgrowth and arachnodactyly.

A census of human RNA-binding proteins.

Abstract: Post-transcriptional gene regulation (PTGR) concerns processes involved in the maturation, transport, stability and translation of coding and non-coding RNAs. RNA-binding proteins (RBPs) and ribonucleoproteins coordinate RNA processing and PTGR. The introduction of large-scale quantitative methods, such as next-generation sequencing and modern protein mass spectrometry, has renewed interest in the investigation of PTGR and the protein factors involved at a systems-biology level. Here, we present a census of 1,542 manually curated RBPs that we have analysed for their interactions with different classes of RNA, their evolutionary conservation, their abundance and their tissue-specific expression. Our analysis is a critical step towards the comprehensive characterization of proteins involved in human RNA metabolism.

Retinoic acid signalling during development

Abstract: Retinoic acid (RA) is a vitamin A-derived, non-peptidic, small lipophilic molecule that acts as ligand for nuclear RA receptors (RARs), converting them from transcriptional repressors to activators. The distribution and levels of RA in embryonic tissues are tightly controlled by regulated synthesis through the action of specific retinol and retinaldehyde dehydrogenases and by degradation via specific cytochrome P450s (CYP26s). Recent studies indicate that RA action involves an interplay between diffusion (morphogen-like) gradients and the establishment of signalling boundaries due to RA metabolism, thereby allowing RA to finely control the differentiation and patterning of various stem/progenitor cell populations. Here, we provide an overview of the RA biosynthesis, degradation and signalling pathways and review the main functions of this molecule during embryogenesis.

tRNA biology charges to the front

Abstract: tRNA biology has come of age, revealing an unprecedented level of understanding and many unexpected discoveries along the way. This review highlights new findings on the diverse pathways of tRNA maturation, and on the formation and function of a number of modifications. Topics of special focus include the regulation of tRNA biosynthesis, quality control tRNA turnover mechanisms, widespread tRNA cleavage pathways activated in response to stress and other growth conditions, emerging evidence of signaling pathways involving tRNA and cleavage fragments, and the sophisticated intracellular tRNA trafficking that occurs during and after biosynthesis.

Retinoic acid in development: towards an integrated view

Abstract: Retinoic acid (RA) has complex and pleiotropic functions during vertebrate development. Recent work in several species has increased our understanding of the roles of RA as a signalling molecule. These functions rely on a tight control of RA distribution within embryonic tissues through the combined action of synthesizing and metabolizing enzymes, possibly leading to diffusion gradients. Also important is the switching of nuclear receptors from a transcriptionally repressing state to an activating state. In addition, cross-talk with other key embryonic signals, especially fibroblast growth factors (FGFs) and sonic hedgehog (SHH), is being uncovered. Some of these functions could be maintained throughout the life of an organism to regulate cell-lineage decisions and/or the differentiation of stem cell populations, highlighting possibilities for regenerative medicine.

The Retinal Pigment Epithelium in Health and Disease

Abstract: Retinal pigment epithelial cells (RPE) constitute a simple layer of cuboidal cells that are strategically situated behind the photoreceptor (PR) cells. The inconspicuousness of this monolayer contrasts sharply with its importance [1]. The relationship between the RPE and PR cells is crucial to sight; this is evident from basic and clinical studies demonstrating that primary dysfunctioning of the RPE can result in visual cell death and blindness. RPE cells carry out many functions including the conversion and storage of retinoid, the phagocytosis of shed PR outer segment membrane, the absorption of scattered light, ion and fluid transport and RPE-PR apposition. The magnitude of the demands imposed on this single layer of cells in order to execute these tasks, will become apparent to the reader of this review as will the number of clinical disorders that take origin from these cells.