Dominant cataract formation in association with a vimentin assembly disrupting mutation

Müller, Martin; Bhattacharya, Siladitya; Moore, T.; Prescott, Quincy; Wedig, Tatjana; Herrmann, Harald; Magin, Thomas M.

doi:10.1093/hmg/ddn440

Cited by 94 publications

(85 citation statements)

References 20 publications

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“…Similarly, mutations in the central rod domain of cytoskeletal IF proteins, such as desmin, keratins, and vimentin, have severe consequences for filament structure and function and cause variety of diseases including skeletal and cardiac myopathies (23), skin blistering diseases (24), and cataracts (25). The E145 residue is in an e position of one of the six heptads within the 42-amino acid sequence that is unique to lamins, and it is predicted to be solvent exposed rather than residing in the coiled-coil interface.…”

Section: Discussionmentioning

confidence: 99%

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

Taimen

Pfleghaar²,

Shimi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

199

215

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Numerous mutations in the humancomprising the major structural components of the nuclear lamina, the fibrous meshwork underlying the inner nuclear membrane (1). They are major determinants of nuclear size and shape and are involved in essential functions such as DNA replication and transcription (1). Lamins A (LA) and C (LC) are alternatively spliced products of the LMNA gene, whereas lamins LB1 and LB2 are encoded by LMNB1 and LMNB2. Structurally, the lamins have a conserved central ␣-helical rod domain flanked by globular head and tail domains. The central rod is responsible for the formation of in-parallel and in-register coiled-coil dimers, the building blocks of lamin polymers. In vitro, lamin dimers form head-to-tail chains, which further interact laterally in an anti-parallel orientation to form highly ordered paracrystals (PCs) (2). However, little is known about the assembly of lamins into higher order structures in vivo.There are Ͼ250 mutations in human LMNA causing a wide range of diseases [for detail, see http//www.umd.be/LMNA/ and (3)]. Among these is the rare premature aging disease, Hutchinson-Gilford progeria syndrome (HGPS). HGPS children typically appear normal at birth, but show growth retardation before the age of 2 years. Further manifestations include loss of hair, lipodystrophy, sclerodermatous skin, osteolysis, and progressive atherosclerosis leading to death at an average age of 13 years due to myocardial infarcts and strokes (4). Most HGPS patients carry the 1824CϾT mutation (G608G), which activates a cryptic splice site resulting in the expression of LA with 50 amino acids deleted near its C terminus (LA⌬50/progerin) (5). As a result, LA⌬50/ progerin remains permanently farnesylated (6, 7), and its accumulation in patients' cells is correlated with the loss of heterochromatin and changes in histone methylation (1).In addition to 1824CϾT, there are 21 other LMNA mutations causing progeria (http://www.umd.be/LMNA/). Some of these are located in the central rod domain, where they could directly impact the assembly of lamins into dimers and higher order structures. Here, we have studied the alterations in nuclear architecture and chromatin organization in one of these mutations, 433GϾA (E145K), located in segment 1B of the central rod domain of LA/C (5). A patient bearing this mutation showed earlier onset cardiovascular defects, only partial loss of hair and ample s.c. fat (5). We show that fibroblasts derived from an E145K patient have severely misshapen nuclei and multiple defects in chromatin organization as reflected by centromere clustering and an abnormal distribution of telomeres throughout the cell cycle. These abnormalities are established during cell division as nuclei assemble in daughter cells. The results demonstrate that the nuclear changes in E145K progeria cells are significantly different from those seen in cells expressing LA⌬50/ progerin, and they also emphasize the essential role of lamins in establishing and maintaining nuclear architecture.

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Section: Discussionmentioning

confidence: 99%

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

Taimen

Pfleghaar²,

Shimi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

199

215

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“…An example of the latter is vimentin, which has recently been associated with cataract formation (29). The broad distribution of vimentin in mesenchymal cells raises the intriguing possibility, which remains to be tested, that disorders involving other cell types (e.g., endothelial and hematopoietic cells) could be modified by vimentin variants.…”

Section: Numerous Opportunities and Challenges In The If Fieldmentioning

confidence: 99%

“IF-pathies”: a broad spectrum of intermediate filament–associated diseases

2009

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Intermediate filaments (IFs) are encoded by the largest gene family among the three major cytoskeletal protein groups. Unique IF compliments are expressed in selective cell types, and this expression is reflected in their involvement, upon mutation, as a cause of or predisposition to more than 80 human tissue-specific diseases. This Review Series covers diseases and functional and structural aspects pertaining to IFs and highlights the molecular and functional consequences of IF-associated diseases (IF-pathies). Exciting challenges and opportunities face the IF field, including developing both a better understanding of the pathogenesis of IF-pathies and targeted therapeutic approaches. Intermediate filamentsIntermediate filaments (IFs), microfilaments (MFs), and microtubules (MTs) are the major fibrillar cytoplasmic elements that make up what is referred to as the cytoskeleton. IFs consist of a large protein family that includes 73 unique gene products, which places the genes encoding them among the 100 largest gene families in humans (1). The IF proteins are grouped into six types (types I-VI): those in types I-IV are found in the cytoplasm, the type V IF proteins are found in the nucleus, and those classified as type VI are found exclusively in the lens (Table 1). Several features distinguish IFs (2-4) from MFs and MTs, including IF structural diversity, tissue- and cell-selective expression, unique subcellular compartment distribution (lamins are found in the nucleus, whereas the remaining IFs are in the cytoplasm), relative insolubility, nucleotide-independent assembly, restricted expression to higher eukaryotes, and, most relevant, their involvement in more than 80 human diseases (Human Intermediate Filament Database, http://www.interfil.org/index.php) (5). Another distinguishing feature of IFs is their regulation (primarily but not exclusively) by phosphorylation, whereas MFs and MTs are regulated preferentially but not exclusively by their associated proteins and posttranslational modifications other than phosphorylation (6). Furthermore, IFs are characteristically resistant to breakage when mechanically stressed, whereas MFs and MTs are far less compliant (7).In addition to the unique and complex cell and tissue distribution of IFs (Figure 1), the expression of some IF proteins is highly regulated during development and cell differentiation and can be markedly induced in cells and tissues undergoing an injury response. For example, keratin 5 and 14 (K5/K14) are found in basal keratinocytes, whereas K1/K10 are found in the differentiating layers of suprabasal epidermis (8); K19 is found in fetal but not normal adult hepatocytes (9); K19/K20 (10) and K6/K16 (11) are highly induced in response to pancreatic acinar cell and skin injury, respectively; and glial fibrillary acidic protein (GFAP) is upregulated during reactive gliosis (12). The Review SeriesThe Review Series herein includes eight state-of-the-art treatises by leaders in the field. The first article, by John Eriksson, Robert Goldman, and colleagu...

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“…These include BFSP1 and BFSP2 (11), vimentin (12,13), glial fibrillary acidic protein (GFAP) (14), simple epithelial keratins (14,15), nestin (16,17), and synemin (18). Of these, vimentin, BFSP1, and BFSP2 are the most highly expressed and also those that when mutated in humans can cause cataracts (6,19). The lens has traditionally been used as a source for vimentin, and subsequently for BFSP1 and BFSP2, for biochemical analyses (20).…”

Section: If Proteins In the Eye Lensmentioning

confidence: 99%

“…Recently, the introduction of an Arg-to-Cys mutation in the LNDR motif in helix 1A of vimentin produced a dominant negative mutant, and mice transgenic for this mutant developed cataract (87). Further, the first vimentin mutation (E151K) to cause cataract in humans has been identified (19). Therefore, there is little doubt that vimentin is important for lens function.…”

Section: Beaded Filaments and Vimentin: A Functional Partnership?mentioning

confidence: 99%

“…Therefore, there is little doubt that vimentin is important for lens function. This could be due to disruption of vimentin assembly caused by the E151K mutation or to increased proteasomal activity (19); these would suggest a dominant gain of function as the underlying mechanism in this cataract phenotype.…”

Section: Beaded Filaments and Vimentin: A Functional Partnership?mentioning

confidence: 99%

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Functions of the intermediate filament cytoskeleton in the eye lens

Song¹,

Landsbury²,

Dahm³

et al. 2009

J. Clin. Invest.

160

107

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Intermediate filaments (IFs) are a key component of the cytoskeleton in virtually all vertebrate cells, including those of the lens of the eye. IFs help integrate individual cells into their respective tissues. This Review focuses on the lens-specific IF proteins beaded filament structural proteins 1 and 2 (BFSP1 and BFSP2) and their role in lens physiology and disease. Evidence generated in studies in both mice and humans suggests a critical role for these proteins and their filamentous polymers in establishing the optical properties of the eye lens and in maintaining its transparency. For instance, mutations in both BFSP1 and BFSP2 cause cataract in humans. We also explore the potential role of BFSP1 and BFSP2 in aging processes in the lens.

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Dominant cataract formation in association with a vimentin assembly disrupting mutation

Cited by 94 publications

References 20 publications

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

“IF-pathies”: a broad spectrum of intermediate filament–associated diseases

Functions of the intermediate filament cytoskeleton in the eye lens

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