The LINC complex and human disease.

The LINC (linker of nucleoskeleton and cytoskeleton) complex is a proposed mechanical link tethering the nucleo- and cyto-skeleton via the NE (nuclear envelope). The LINC components emerin, lamin A/C, SUN1, SUN2, nesprin-1 and nesprin-2 interact with each other at the NE and also with other binding partners including actin filaments and B-type lamins. Besides the mechanostructural functions, the LINC complex is also involved in signalling pathways and gene regulation. Emerin was the first LINC component associated with a human disease, namely EDMD (Emery-Dreifuss muscular dystrophy). Later on, other components of the LINC complex, such as lamins A/C and small isoforms of nesprin-1 and nesprin-2, were found to be associated with EDMD, reflecting a genetic heterogeneity that has not been resolved so far. Only approximately 46% of the EDMD patients can be linked to genes of LINC and non-LINC components, pointing to further genes involved in the pathology of EDMD. Obvious candidates are the LINC proteins SUN1 and SUN2. Recently, screening of binding partners of LINC components as candidates identified LUMA (TMEM43), encoding a binding partner of emerin and lamins, as a gene involved in atypical EDMD. Nevertheless, such mutations contribute only to a very small fraction of EDMD patients. EDMD-causing mutations in STA/EMD (encoding emerin) that disrupt emerin binding to Btf (Bcl-2-associated transcription factor), GCL (germ cell-less) and BAF (barrier to autointegration factor) provide the first glimpses into LINC being involved in gene regulation and thus opening new avenues for functional studies. Thus the association of LINC with human disease provides tools for understanding its functions within the cell.

Restrictive dermopathy. Molecular diagnosis of restrictive dermopathy in a stillborn fetus from a consanguineous Iranian family.

Restrictive dermopathy (RD), is an autosomal recessive lethal human genetic disorder. It is characterized by intrauterine growth retardation, tight and rigid skin with erosions, multiple joint contractures, lung hypoplasia, prominent superficial vasculature, and epidermal hyperkeratosis. In the present report, we describe the first case of restrictive dermopathy in a stillborn fetus of Iranian origin, confirmed by molecular genetic diagnosis. In the index case (G-30159), a homozygous one base insertion in ZMPSTE24 exon 9 (c.1085-1086insT) was identified.We believe that by increasing awareness of this disease in clinicians, gynecologists, and pathologists, we may be able to help families who have had suspected cases of restrictive dermopathy be diagnosed, and offer molecular testing in carriers, and prenatal diagnosis to prevent the occurrence of further affected cases.

Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy.

The familial form of dilated cardiomyopathy (DCM) occurs in about 20%-50% of DCM cases. It is a heterogeneous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most important disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician.

Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery-Dreifuss muscular dystrophy.

Mutations in the LMNA gene encoding the nuclear envelope protein, lamins A and C, have been associated with at least nine distinct disorders now called laminopathies, including Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth type 2 disease. We identified a novel mutation in the 5' region of the LMNA gene -3del15, resulting in the loss of 15 nucleotides from -3 to +12, including the translation ATG initiator codon. The mutation segregates in a previously described family with a clinical phenotype that shared features of both Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth type 2. Thus, the mutation with this unique phenotypical expression represents the first example for a link between the neurogenic and myogenic phenotypes and extends the clinical variability of laminopathies.

Early onset of cardiomyopathy in two brothers with X-linked Emery-Dreifuss muscular dystrophy.

Two brothers are reported suffering from X-linked Emery-Dreifuss muscular dystrophy caused by a 59bp deletion eliminating nucleotides 329-388 of the STA gene. Besides the typical findings for Emery-Dreifuss muscular dystrophy, both patients showed an unusual early onset of cardiac symptoms at age 6 and 9 years, respectively, coinciding with unusual high creatine kinase. A cardiological follow up showed worsening of the cardiac condition in the beginning of the second decade. The two boys described here belong to the very few Emery-Dreifuss muscular dystrophy patients with early onset of cardiac involvement and contribute to the variability of cardiac symptoms in Emery-Dreifuss muscular dystrophy.

The nuclear muscular dystrophies.

Nuclear muscular dystrophies are referred to as inherited muscular dystrophies caused by mutations in genes--(STA) or lamina (LMNA)--encoding components of the nuclear envelope. Phenotypically, they present as Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscle dystrophy 1B (LGMD1B), or dilated cardiomyopathy with conduction defects (DCM-CD). Genetically related are the Dunnigan-type of familial partial lipodystrophy (FPLD) and Charcot-Marie-Tooth neuropathy type 2 (CMT2B). Until now, approximately 70 unique STA mutations, leading to X-linked EDMD or DCM-CD, have resulted mostly in a complete lack of emerin. Further 50 mostly missense mutations in LMNA result in autosomal-dominant EDMD, autosomal-recessive EDMD, LGMD1B, DCM-CD, FPLD, or CMT2B. Independent of type or location of the mutations, emerinopathies and laminopathies show wide clinical intrafamilial and interfamilial variability. Although structural abnormalities of nuclei in animal and cell models have been observed, the molecular pathology of the nuclear muscular dystrophies needs still to be elucidated.