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De novo heterozygous FBN1 mutations in the extreme C-terminal region cause progeroid fibrillinopathy.

Published on May 1, 2014in American Journal of Medical Genetics Part A
· DOI :10.1002/AJMG.A.36449
Abhimanyu Garg14
Estimated H-index: 14
(UTSW: University of Texas Southwestern Medical Center),
Chao Xing31
Estimated H-index: 31
Abstract
  • References (11)
  • Citations (14)
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References11
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#1Toshiki Takenouchi (Keio: Keio University)H-Index: 15
#2Mariko Hida (Keio: Keio University)H-Index: 14
Last. Kenjiro Kosaki (Keio: Keio University)H-Index: 34
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Recently, three marfanoid patients with congenital lipodystrophyandaneonatalprogeroidappearancewerereported.AlthoughtheirphenotypewasdistinctfromthatofclassicMarfansyndrome,theyallhadatruncatingmutationinthepenultimateexon,i.e.,exon64,of FBN1,thecausativegeneforMarfansyndrome.Thesepatientsmight represent a new entity, but the exact phenotypic and geno-typic spectrum remains unknown. Here, we report on a girl bornprematurely who exhibited severe congenital lipodystrophy and aneonatalprogeroid app...
33 CitationsSource
#1Paddy M. Barrett (Scripps Health)H-Index: 8
#2Eric J. Topol (Scripps Health)H-Index: 179
The dramatic reductions in DNA sequencing costs allow us to delve deeper into the genomic alterations that increase susceptibility to many polygenic cardiovascular diseases. One such condition is an abnormal proximal aorta. Until recently, many believed that dilated, distorted or dissected proximal aortas might represent a forme fruste of Marfan syndrome or a continuum of aortopathy. Although an FBN-1 mutation does not guarantee the diagnosis of Marfan syndrome it is clear however that FBN-1 mut...
12 CitationsSource
#1Rebecca L. Margraf (ARUP Laboratories)H-Index: 18
#2Patti KrautscheidH-Index: 4
Last. Rong MaoH-Index: 27
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A patient with an apparent sporadic medullary thyroid carcinoma was tested for RET germline mutations by Sanger sequencing of RET exons 10, 11, and 13-16. The patient was heterozygous for two known mutations causative of Multiple Endocrine Neoplasia type 2 disorder, and both mutations were within codon 620 of RET exon 10, c.1859G > T (p.C620F) and c.1860C > G (p.C620W). In order to determine if these adjacent mutations were in cis or in trans, an unlabeled probe method and high-resolution meltin...
1 CitationsSource
#1Sacha A. Jensen (University of Oxford)H-Index: 16
#2Ian B. Robertson (University of Oxford)H-Index: 10
Last. Penny A. Handford (University of Oxford)H-Index: 41
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Force-bearing tissues such as blood vessels, lungs, and ligaments depend on the properties of elasticity and flexibility. The 10 to 12 nm diameter fibrillin microfibrils play vital roles in maintaining the structural integrity of these highly dynamic tissues and in regulating extracellular growth factors. In humans, defective microfibril function results in several diseases affecting the skin, cardiovascular, skeletal, and ocular systems. Despite the discovery of fibrillin-1 having occurred more...
60 CitationsSource
#1Jack Goldblatt (UWA: University of Western Australia)H-Index: 46
#2Jill Hyatt (UWA: University of Western Australia)H-Index: 1
Last. Ian Walpole (ECU: Edith Cowan University)H-Index: 13
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We report on a 20-year-old man who presented in infancy with severe generalized lipodystrophy with a progeroid appearance and some Marfanoid features. He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene. This analysis showed him to have a novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene. His phenotype is similar to a patient described by Graul-Neumann et al. [...
29 CitationsSource
#1Denise Horn (Charité)H-Index: 39
#2Peter N. Robinson (MPG: Max Planck Society)H-Index: 62
Last. Peter A. Robinson (MPG: Max Planck Society)H-Index: 52
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The association of progeroid features and lipodystrophy was very recently described in a female adult with additional manifestations of Marfan syndrome. Mutation analysis of the fibrillin I (FBN1) gene revealed a novel heterozygous frameshift mutation at the 3′ end in that patient. Here, we report on a 3.5-year-old girl with progeroid facial signs of neonatal onset, lipodystrophy, large head circumference with corresponding hydrocephaly, and tall stature at the end of infancy. Her facial appeara...
28 CitationsSource
#1Luitgard Graul-Neumann (Charité)H-Index: 19
#2Tina Kienitz (Charité)H-Index: 8
Last. Eberhard PassargeH-Index: 29
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We report on a 25-year-old woman with pronounced generalized lipodystrophy and a progeroid aspect since birth, who also had Marfan syndrome (MFS; fulfilling the Ghent criteria) with mild skeletal features, dilated aortic bulb, dural ectasia, bilateral subluxation of the lens, and severe myopia in addition to the severe generalized lipodystrophy. She lacked insulin resistance, hypertriglyceridemia, hepatic steatosis, and diabetes. Mutation analysis in the gene encoding fibrillin 1 (FBN1) revealed...
39 CitationsSource
#1Delphine DetaintH-Index: 32
#2Laurence FaivreH-Index: 59
Last. Guillaume Jondeau (French Institute of Health and Medical Research)H-Index: 40
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Aims In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease. This study evaluates the cardiovascular (CV) risk associated with the discovery of a fibrillin-1 (FBN1) mutation. Methods and results A total of 1013 probands with pathogenic FBN1 mutations were included, among whom 965 patients [median age: 22 years (11– 34), male gender 53%] had data suitable ...
77 CitationsSource
#1Brendan O'Neill (UTSW: University of Texas Southwestern Medical Center)H-Index: 1
#2Vinaya Simha (UTSW: University of Texas Southwestern Medical Center)H-Index: 20
Last. Abhimanyu GargH-Index: 64
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Neonatal progeroid syndrome (NPS), also known as Wiedemann–Rautenstrauch Syndrome, is a rare autosomal recessive disorder characterized by accelerated aging and lipodystrophy from birth. Affected children have extreme intrauterine growth retardation, poor postnatal weight gain, and characteristic facial dysmorphic features such as a triangular shape, pinched nose, pseudohydrocephalus with wide fontanelles and prominent subcutaneous (sc) veins. Generalized loss of sc fat has been reported as a ca...
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#1Patrick Rump (UMCG: University Medical Center Groningen)H-Index: 24
#2Tom G.W. Letteboer (UU: Utrecht University)H-Index: 15
Last. Essen van A. J (UMCG: University Medical Center Groningen)H-Index: 19
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We describe a unique case of achondroplasia with associated complications, including severe respiratory problems. Molecular analysis of the fibroblast growth factor receptor type 3 (FGFR3) gene in this patient showed the common p.G380R mutation and a second novel p.L377R mutation. An allele-specific PCR demonstrated that these mutations were on the same allele (cis). Both mutations were not present in the parents and appear to have occurred de novo. To our knowledge, this is the first report in ...
14 CitationsSource
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#2Dieter P. Reinhardt (McGill University)H-Index: 43
The extracellular matrix microenvironment of adipose tissue is of critical importance for the differentiation, remodeling and function of adipocytes. Fibrillin-1 is one of the main components of microfibrils and a key player in this process. Furin processing of profibrillin-1 results in mature fibrillin-1 and releases the C-terminal propeptide as a circulating hunger hormone, asprosin. Mutations in the fibrillin-1 gene lead to adipose tissue dysfunction and causes Marfan syndrome, marfanoid prog...
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#1Mao Lin (Peking Union Medical College)H-Index: 3
#1Mao Lin (Peking Union Medical College)
Last. Nan Wu (Peking Union Medical College)H-Index: 15
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BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, ...
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#1Helga V. Toriello (MSU: Michigan State University)H-Index: 29
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#1Nan Wu (Peking Union Medical College Hospital)H-Index: 15
#2Mao Lin (Peking Union Medical College Hospital)H-Index: 3
Last. Jianguo Zhang (Peking Union Medical College Hospital)H-Index: 15
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The molecular and genetic mechanisms by which different single nucleotide variant (SNV) alleles in specific genes, or at the same genetic locus, bring about distinct disease phenotypes often remain unclear. Allelic truncating mutations of fibrillin-1 (FBN1) cause either classical Marfan syndrome (MFS) or a more severe phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). A total of three Marfan syndrome/Marfanoid patients (2 singletons and 1 parent-offspring trio) were rec...
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#1Jennifer A. Wambach (WashU: Washington University in St. Louis)H-Index: 13
#2Daniel J. Wegner (WashU: Washington University in St. Louis)H-Index: 13
Last. Abhimanyu Garg (UTSW: University of Texas Southwestern Medical Center)H-Index: 14
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Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and...
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#1Mao Chen (JLU: Jilin University)H-Index: 9
#2Bing Yao (JLU: Jilin University)H-Index: 1
Last. Liangxue Lai (JLU: Jilin University)H-Index: 48
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Variable clinical differences have been observed between the FBN1 gene mutation and the classical Marfan phenotype in humans. Although FBN1 knockout (KO), or dominant negative mutant mice are widely used as an animal model for MFS, these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy syndrome (MPL), a syndrome caused by a mutation in the C-terminus of fibrillin-1, the penultimate exon of the FBN1 gene. Here we describe the generation of a rabbit...
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#1Stefano Paolacci (Sapienza University of Rome)H-Index: 6
#1Stefano Paolacci (Sapienza University of Rome)H-Index: 2
Last. Raoul C.M. Hennekam (UvA: University of Amsterdam)H-Index: 84
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Wiedemann–Rautenstrauch syndrome (WRS) is a neonatal progeroid disorder characterized by growth retardation, lipodystrophy, a distinctive face, and dental anomalies. Patients reported to date demonstrate a remarkable variability in phenotype, which hampers diagnostics. We performed a literature search, and analyzed 51 reported patients, using the originally reported patients as “gold standard.” In 15 patients sufficient information and photographic evidence was available to confirm the clinical ...
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#1Lynn Y. Sakai (OHSU: Oregon Health & Science University)H-Index: 66
#2Douglas R. Keene (OHSU: Oregon Health & Science University)H-Index: 79
Last. De Backer J (Ghent University Hospital)H-Index: 1
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Abstract FBN1 encodes the gene for fibrillin-1, a structural macromolecule that polymerizes into microfibrils. Fibrillin microfibrils are morphologically distinctive fibrils, present in all connective tissues and assembled into tissue-specific architectural frameworks. FBN1 is the causative gene for Marfan syndrome, an inherited disorder of connective tissue whose major features include tall stature and arachnodactyly, ectopia lentis, and thoracic aortic aneurysm and dissection. More than one th...
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#1Eberhard PassargeH-Index: 29
#2Peter A. Robinson (Charité)H-Index: 52
Last. Luitgard Graul-Neumann (Charité)H-Index: 19
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We review six previous reports between 2000 and 2014 of seven unrelated patients with mutations in the FBN1 gene affecting function. All mutations occurred in exon 64 of the FBN1 gene. A distinctive phenotype consisting of partial manifestations of Marfan syndrome, a progeroid facial appearance, and clinical features of lipodystrophy was present in all individuals. We suggest that this previously unknown genotype/phenotype relationship constitutes a new fibrillinopathy for which the name marfano...
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