共查询到20条相似文献,搜索用时 31 毫秒
1.
Wopereis S Morava E Grünewald S Mills PB Winchester BG Clayton P Coucke P Huijben KM Wevers RA 《Biochimica et biophysica acta》2005,1741(1-2):156-164
Based on our preliminary observation of abnormal glycosylation in a cutis laxa patient, nine cutis laxa patients were analyzed for congenital defects of glycosylation (CDG). Isoelectric focusing of plasma transferrin and apolipoproteinC-III showed that three out of nine patients had a defect in the biosynthesis of N-glycans and core 1 mucin type O-glycans, respectively. Mass spectrometric N-glycan analyses revealed a relative increase of glycans lacking sialic acid and glycans lacking sialic acid and galactose residues. Mutation analysis of the fibulin-5 gene (FBLN5), which has been reported in cases of autosomal recessive cutis laxa, revealed no mutations in the patients' DNA. Evidence is presented that extracellular matrix (ECM) proteins of skin are likely to be highly glycosylated with N- and/or mucin type O-glycans by using algorithms for predicting glycosylation. The conclusions in this study were that the clinical phenotype of autosomal recessive cutis laxa seen in three patients is not caused by mutations in the FBLN5 gene. Our findings define a novel form of CDG with cutis laxa and neurological involvement due to a defect in the sialylation and/or galactosylation of N- and O-glycans. Improper glycosylation of ECM proteins of skin may form the pathophysiological basis for the cutis laxa phenotype. 相似文献
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Masato Tsukahara Hiroshi Shinkai Chidori Asagami Tsuyako Eguchi Tadashi Kajii 《Human genetics》1988,78(1):9-12
Summary A mother and daughter are described with light and electron microscopic, and biochemical abnormalities of their connective tissue characteristic of both cutis laxa and the Ehlers-Danlos syndrome. The mother was clinically normal, while her 8-year-old daughter exhibited loose, wrinkled skin and other clinical features of cutis laxa, and also fragility, bruisability and hyper-extensibility of the skin and poor healing of wounds, leaving cigarette paper scars, features characteristic of the Ehlers-Danlos syndrome. Light and electron microscopic studies of skin biopsy specimens and cultured skin fibroblasts from both individuals revealed reduced and distorted elastic fibres, a finding usually seen in cutis laxa. Electrophoretic studies of collagen excreted from cultured skin fibrobasts revealed in both individuals and alpha 2(I) chain with a molecular size smaller than usual. The father and elder daughter were normal by clinical, light and electron microscopic and electrophoretic studies. It was concluded from these findings that the mother and daughter represented a hitherto undescrbed disease of the connective tissue with dominant inheritance and variable expressivity. 相似文献
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Delfien Syx Fransiska Malfait Lut Van Laer Jan Hellemans Trinh Hermanns-Lê Andy Willaert Abdelmajid Benmansour Anne De Paepe Alain Verloes 《Human genetics》2010,128(1):79-88
Defects leading to impaired intracellular trafficking have recently been shown to play an important role in the pathogenesis
of genodermatoses, such as the Ehlers–Danlos and the cutis laxa syndromes. A new genodermatosis, termed macrocephaly, alopecia,
cutis laxa and scoliosis (MACS) syndrome has been described, resulting from a homozygous 1-bp deletion in RIN2. RIN2 encodes the Ras and Rab interactor 2, involved in the regulation of Rab5-mediated early endocytosis. We performed a clinical,
ultrastructural and molecular study in a consanguineous Algerian family with three siblings affected by a distinctive autosomal
recessive genodermatosis, reported in 2005 by Verloes et al. The most striking clinical features include progressive facial
coarsening, gingival hypertrophy, severe scoliosis, sparse hair and skin and joint hyperlaxity. Ultrastructural studies of
the skin revealed important abnormalities in the collagen fibril morphology, and fibroblasts exhibited a dilated endoplasmic
reticulum and an abnormal Golgi apparatus with rarefied and dilated cisternae. Molecular analysis of RIN2 revealed a novel homozygous 2-bp deletion in all affected individuals. The c.1914_1915delGC mutation introduces a frameshift
and creates a premature termination codon, leading to nonsense-mediated mRNA decay. These findings confirm that RIN2 defects are associated with a distinct genodermatosis and underscore the involvement of RIN2 and its associated pathways in the pathogenesis of connective tissue disorders. The current family displays considerable
phenotypic overlap with MACS syndrome. However, our family shows a dermatological and ultrastructural phenotype belonging
to the Ehlers–Danlos rather than the cutis laxa spectrum. Therefore, the MACS acronym is not entirely appropriate for the
current family. 相似文献
6.
Mailys Guillard Aikaterini Dimopoulou Björn Fischer Eva Morava Dirk J. Lefeber Uwe Kornak Ron A. Wevers 《生物化学与生物物理学报:疾病的分子基础》2009,1792(9):903-914
Glycosylation of proteins is one of the most important post-translational modifications. Defects in the glycan biosynthesis result in congenital malformation syndromes, also known as congenital disorders of glycosylation (CDG). Based on the iso-electric focusing patterns of plasma transferrin and apolipoprotein C-III a combined defect in N- and O-glycosylation was identified in patients with autosomal recessive cutis laxa type II (ARCL II). Disease-causing mutations were identified in the ATP6V0A2 gene, encoding the a2 subunit of the vacuolar H+-ATPase (V-ATPase). The V-ATPases are multi-subunit, ATP-dependent proton pumps located in membranes of cells and organels. In this article, we describe the structure, function and regulation of the V-ATPase and the phenotypes currently known to result from V-ATPase mutations. A clinical overview of cutis laxa syndromes is presented with a focus on ARCL II. Finally, the relationship between ATP6V0A2 mutations, the glycosylation defect and the ARCLII phenotype is discussed. 相似文献
7.
《American journal of human genetics》2015,97(3):483-492
Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling. 相似文献
8.
Prof. Dr. U. Kornak 《Medizinische Genetik》2012,24(4):273-278
All autosomal recessive cutis laxa syndromes display more or less pronounced progeroid features. Common hallmarks include the altered connective tissue that underlies the wrinkled, lax skin and a variable reduction in bone mineral density. Depending on the subtype, other symptoms such as abnormal hair or cardiovascular, neurological, gastrointestinal and urological problems may arise. This article gives an overview of the clinical characteristics, gene defects and current knowledge concerning their pathological mechanisms. 相似文献
9.
Bj?rn Fischer Aikaterini Dimopoulou Johannes Egerer Thatjana Gardeitchik Alexa Kidd Dominik Jost Hülya Kayserili Yasemin Alanay Iliana Tantcheva-Poor Elisabeth Mangold Cornelia Daumer-Haas Shubha Phadke Reto I. Peirano Julia Heusel Charu Desphande Neerja Gupta Arti Nanda Emma Felix Elisabeth Berry-Kravis Madhulika Kabra Ron A. Wevers Lionel van Maldergem Stefan Mundlos Eva Morava Uwe Kornak 《Human genetics》2012,131(11):1761-1773
Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H+-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients’ dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-β signalling and increased TGF-β1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL. 相似文献
10.
Qirui Hu Adrian Shifren Carla Sens Jiwon Choi Zoltan Szabo Barry C. Starcher Russell H. Knutsen J. Michael Shipley Elaine C. Davis Robert P. Mecham Zsolt Urban 《Matrix biology》2010,29(7):621-628
Heterozygous elastin gene mutations cause autosomal dominant cutis laxa associated with emphysema and aortic aneurysms. To investigate the molecular mechanisms leading to cutis laxa in vivo, we generated transgenic mice by pronuclear injection of minigenes encoding normal human tropoelastin (WT) or tropoelastin with a cutis laxa mutation (CL). Three independent founder lines of CL mice showed emphysematous pulmonary airspace enlargement. No consistent dermatological or cardiovascular pathologies were observed. One CL and one WT line were selected for detailed studies. Both mutant and control transgenic animals showed elastin deposition into pulmonary elastic fibers, indicated by increased desmosine levels in the lung and by colocalization of transgenic and endogenous elastin by immunostaining. CL mice showed increased static lung compliance and decreased stiffness of lung tissue. In addition, markers of transforming growth factor-β (TGFβ) signaling and the unfolded protein response (UPR) were elevated together with increased apoptosis in the lungs of CL animals. We conclude that the synthesis of mutant elastin in CL activates multiple downstream disease pathways by triggering a UPR, altered mechanical signaling, increased release of TGFβ and apoptosis. We propose that the combined effects of these processes lead to the development of an emphysematous pulmonary phenotype in CL. 相似文献
11.
Leprechaunism is a very rare condition of obscure etiology. Since the first report (Donohue, 1948) 48 patients have been described. The typical stigmata are a "gnome" facies with a saddle nose, broad mouth, large and low-set ears, hirsutism, cutis laxa with atrophy of adipose tissue, dwarfism, extreme wasting, and dysphagia requiring parenteral feeding. After reviewing the literature and discussing the morphological, biological, and etiopathogenetic aspects, the authors conclude that the diagnosis of leprechaunism is essentially a clinic one, as there are no specific laboratory tests. 相似文献
12.
LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Identify and describe the anatomy of and changes to the aging face, including changes in bone mass and structure and changes to the skin, tissue, and muscles. 2. Assess each individual's unique anatomy before embarking on face-lift surgery and incorporate various surgical techniques, including fat grafting and other corrective procedures in addition to shifting existing fat to a higher position on the face, into discussions with patients. 3. Identify risk factors and potential complications in prospective patients. 4. Describe the benefits and risks of various techniques. SUMMARY: The ability to surgically rejuvenate the aging face has progressed in parallel with plastic surgeons' understanding of facial anatomy. In turn, a more clear explanation now exists for the visible changes seen in the aging face. This article and its associated video content review the current understanding of facial anatomy as it relates to facial aging. The standard face-lift techniques are explained and their various features, both good and bad, are reviewed. The objective is for surgeons to make a better aesthetic diagnosis before embarking on face-lift surgery, and to have the ability to use the appropriate technique depending on the clinical situation. 相似文献
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Hucthagowder V Sausgruber N Kim KH Angle B Marmorstein LY Urban Z 《American journal of human genetics》2006,78(6):1075-1080
Cutis laxa is a condition characterized by redundant, pendulous, and inelastic skin. We identified a patient with recessive inheritance of a missense mutation (169G-->A; E57K) in the Fibulin-4 gene. She had multiple bone fractures at birth and was diagnosed with cutis laxa, vascular tortuosity, ascending aortic aneurysm, developmental emphysema, inguinal and diaphragmatic hernia, joint laxity, and pectus excavatum by age 2 years. Her skin showed markedly underdeveloped elastic fibers, and the extracellular matrix laid down by her skin fibroblasts contained dramatically reduced amounts of fibulin-4. We conclude that fibulin-4 is necessary for elastic fiber formation and connective tissue development. 相似文献
15.
M. Mohamed M. Guillard S.B. WortmannS. Cirak E. MarklovaH. Michelakakis E. KorschM. Adamowicz B. KoletzkoF.J. van Spronsen K.E. Niezen-KoningG. Matthijs T. Gardeitchik D. Kouwenberg B. Chan LimR. Zeevaert R.A. WeversD.J. Lefeber E. Morava 《生物化学与生物物理学报:疾病的分子基础》2011,1812(6):691-698
Dysmorphic features, multisystem disease, and central nervous system involvement are common symptoms in congenital disorders of glycosylation, including several recently discovered Golgi-related glycosylation defects. In search for discriminative features, we assessed eleven children suspected with a Golgi-related inborn error of glycosylation. We evaluated all genetically unsolved patients, diagnosed with a type 2 transferrin isofocusing pattern in the period of 1999-2009. By combining biochemical results with characteristic clinical symptoms, we used a diagnostic flow chart to approach the underlying defect in patients with congenital disorders of glycosylation-IIx. According to specific symptoms and laboratory results, we initiated additional, targeted biochemical and genetic studies. We found a distinctive spectrum of congenital disorders of glycosylation type 2-associated anomalies including sudden hearing loss, brain malformations, wrinkled skin, and epilepsy in combination with skeletal dysplasia, dilated cardiomyopathy, sudden cardiac arrest, abnormal copper and iron metabolism, and endocrine abnormalities in our patients. One patient with severe cortical malformations and mild skin abnormalities was diagnosed with a known genetic syndrome, due to an ATP6V0A2 defect. Here, we present unique congenital disorders of glycosylation type 2-associated anomalies, including both ATPase-related and unrelated cutis laxa and sensorineural hearing loss, a recently recognized symptom of congenital disorders of glycosylation. Based on our findings, we recommend clinicians to consider congenital disorders of glycosylation in patients with cardiac rhythm disorders, spondylodysplasia and biochemical abnormalities of the copper and iron metabolism even in absence of intellectual disability. 相似文献
16.
Catherine R. Begy Herman A. Dierick Jeffrey W. Innis Thomas W. Glover 《Human genetics》1995,96(3):355-356
Two highly polymorphic CA repeats have been identified in the Menkes gene (ATP7A). These repeats should be useful for prenatal diagnosis and carrier detection in families with Menkes disease and X-linked cutis laxa. The observed heterozygosity for these two repeats was 0.778 and 0.60 in Centre d'Etude du Polymorphisme Humaine (CEPH) families. 相似文献
17.
D. Bonneau J. L. Huret G. Godeau D. Couet M. Putterman J. Tanzer P. Babin M. Larrègue 《Human genetics》1991,87(3):317-319
Summary A 6-week-old girl presented with cutis laxa, emphysema, heart anomalies and a diaphragmatic hernia. She died at 22 weeks. A recurrent ctb(7)(q31.3) was found and the laminin gene was suspected to be involved in the disease. Anti-human laminin antiserum showed that this protein was absent from the skin. This case, together with 17 other similar cases, could represent a new type of connective tissue disease. 相似文献
18.
Joan E. Pellegrino Rhonda E. Schnur Leslie Boghosian-Sell Gordon Strathdee Joan Overhauser Nancy B. Spinner Tammy Stump Kimberly Grace Elaine H. Zackai 《Human genetics》1996,97(4):532-536
The ablepharon-macrostomia (AMS) and Barber-Say syndromes (BSS) are rare disorders characterized by absence of the eyelids
or ectropion, macrostomia, ambiguous genitalia, abnormal ears, rudimentary nipples, and dry, redundant skin. Patients with
Barber-Say syndrome also have hypertrichosis. We present a patient with a phenotype similar to AMS who has a complex rearrangement
of chromosome 18, involving both an inversion and interstitial deletion. Our patient lacks the typical features of the 18q
deletion syndrome. We review AMS and BSS as compared with our patient, and recognize cutis laxa as a feature shared by all.
We propose that the gene(s) for this phenotype may lie on chromosome 18 in the region of the deletion or inversion breakpoints.
Received: 1 March 1995 / Revised: 20 May 1995 相似文献
19.
Genetic disorders of the elastic fiber system. 总被引:5,自引:0,他引:5
Over the last decade, a considerable amount of new information has emerged describing the protein components of elastic fibers. It is now evident that elastic fibers are complex extracellular matrix polymers, composed of at least 19 different proteins that comprise both the microfibrillar and the amorphous components of elastic fibers. Mutations in three of the genes encoding the most abundant of these elastic fiber proteins result in a broad spectrum of elastic tissue phenotypes, ranging from skeletal and skin abnormalities to vascular and ocular defects. The following disorders will be discussed in this review: supravalvular aortic stenosis; Williams-Beuren syndrome; cutis laxa; Marfan syndrome; ectopia lentis; familial thoracic aortic aneurysms and dissections; MASS syndrome; isolated skeletal features of Marfan syndrome; Shprintzen-Goldberg syndrome; and congenital contractural arachnodactyly. 相似文献
20.
Duane L. Guernsey Susan C. Evans Makoto Matsuoka Andrea L. Rideout Karen Bedard Marie-Pierre Dubé Mark E. Samuels 《American journal of human genetics》2009,85(1):120-129
Autosomal-recessive cutis laxa type 2 (ARCL2) is a multisystem disorder characterized by the appearance of premature aging, wrinkled and lax skin, joint laxity, and a general developmental delay. Cutis laxa includes a family of clinically overlapping conditions with confusing nomenclature, generally requiring molecular analyses for definitive diagnosis. Six genes are currently known to mutate to yield one of these related conditions. We ascertained a cohort of typical ARCL2 patients from a subpopulation isolate within eastern Canada. Homozygosity mapping with high-density SNP genotyping excluded all six known genes, and instead identified a single homozygous region near the telomere of chromosome 17, shared identically by state by all genotyped affected individuals from the families. A putative pathogenic variant was identified by direct DNA sequencing of genes within the region. The single nucleotide change leads to a missense mutation adjacent to a splice junction in the gene encoding pyrroline-5-carboxylate reductase 1 (PYCR1). Bioinformatic analysis predicted a pathogenic effect of the variant on splice donor site function. Skipping of the associated exon was confirmed in RNA from blood lymphocytes of affected homozygotes and heterozygous mutation carriers. Exon skipping leads to deletion of the reductase functional domain-coding region and an obligatory downstream frameshift. PYCR1 plays a critical role in proline biosynthesis. Pathogenicity of the genetic variant in PYCR1 is likely, given that a similar clinical phenotype has been documented for mutation carriers of another proline biosynthetic enzyme, pyrroline-5-carboxylate synthase. Our results support a significant role for proline in normal development. 相似文献