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Compound Heterozygosity for Mutations in LMNA in a Patient with a Myopathic and Lipodystrophic Mandibuloacral Dysplasia Type A Phenotype

Departments of Biopathology and Diagnostic Imaging (F.L., F.G., A.F., A.V., A.M.N., M.R.D., G.N.), Internal Medicine (M.D., V.G., P.S.), and Diagnostic Imaging and Interventional Radiology (S.M.), University of Rome Tor Vergata, 00133 Rome, Italy; Institute of Molecular Genetics-Consiglio Nazionale dell Ricerche (M.C., G.L., N.M.M.), Unit of Bologna, c/o Istituti Ortopedici Rizzoli, 40136 Bologna, Italy; Laboratory of Rheumatology (V.A.) and Laboratory of Medical Genetics (E.G.), Azienda Ospedaliera San Giovanni Battista Torino, 10123 Torino, Italy; Fondazione Livio Patrizi (G.N.), 00100 Rome, Italy; and Department of Cardiovascular Medicine (G.N.), University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Professor Giuseppe Novelli, Department of Biopathology and Diagnostic Imaging, University of Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail: novelli{at}med.uniroma2.it.

	Abstract

Top Abstract Introduction Patient and Methods Results Discussion References

 
Context: Mandibuloacral dysplasia type A (MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation (p.R527H) in the C-terminal tail domain of the LMNA gene, which encodes lamin A/C, an intermediate filament component of the nuclear envelope.

Objective: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics (bird-like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well-known patients.

Design: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated.

Patient: We report a 27-yr-old Italian woman showing a MADA-like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy.

Results: We identified a patient compound heterozygote for the p.R527H and p.V440M alleles. The patient’s cells showed nuclear shape abnormalities, accumulation of pre-lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein-1ß and histone H3 methylated at lysine 9.

Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p.R527H and p.V440M alleles.

	Introduction

Top Abstract Introduction Patient and Methods Results Discussion References

 
MANDIBULOACRAL DYSPLASIA with type A lipodystrophy (MADA; OMIM 248370) is an autosomal recessive disorder characterized by postnatal growth retardation, mandibular hypoplasia, bird-like facies, progressive osteolysis of the terminal phalanges and clavicles, partial lipodystrophy, and metabolic complications associated with insulin resistance, glucose intolerance, diabetes mellitus and hypertriglyceridemia (1, 2, 3). MADA belongs to the primary laminopathies, which include skeletal muscle and cardiac conditions, peripheral nerve disorders, and premature ageing syndromes (4, 5, 6). These disorders are due to abnormalities in the LMNA gene, which encodes nuclear lamina proteins, lamins A/C. They interact with chromatin (7, 8) and the cytoskeleton (9) and are involved in many fundamental cellular processes (6). So it is not surprising that complex patterns of tissue-specific pathologies are associated with lamin defects in humans.

The majority of MADA patients are homozygote for the p.R527H mutation in the LMNA gene (10). However, five Indian subjects carrying the p.K542N homozygous mutation, two Turkish patients with p.A529V mutation in homozygous, and one MAD female compound heterozygote for p.R527C/p.R471C mutations were described (11, 12).

Here we describe a 27-yr-old Italian woman with an apparent MADA phenotype associated with muscular hyposthenia and generalized hypotonia. She was a compound heterozygote for with the p.R527H mutation and the p.V440M allele of the LMNA gene.

	Patient and Methods

Top Abstract Introduction Patient and Methods Results Discussion References

 
Patient

The 27-yr-old Italian proband (Fig. 1A) is the daughter of healthy unrelated parents. Development was normal. At the age of 22 yr, she had a normal pregnancy. After delivery, the patient reported an episode of back pain and stiffness with generalized hypotonia. In 2005 a clinical diagnosis of limb-girdle myopathy was suggested. However, no mutations or variants were detected in the CAPN3 gene. The patient evaluation showed a body mass index of 18.1 kg/m². A dual-energy x-ray absorptiometry scan (Hologic Delphi W densitometer; Hologic, Inc., Waltham, MA) of lumbar and femoral neck regions revealed a low bone mass at these sites (Z-score –2.0 and –2.8 SD, respectively). The milder acroosteolysis (x-ray) and abdominal, neck, and thigh fat distribution [magnetic resonance imaging (MRI) technique, Tesla imaging device; Philips Medical Systems, Best, The Netherlands] are shown in Fig. 1, C, E, G, and I. Dual-energy x-ray absorptiometry scan measurement revealed a whole-body fat mass of 17.7%, segmental distribution showing a leg fat mass of 15.3%, and higher truncal values (20%). Neurological examination showed hyposthenia of the thoracic girdle, a slight waddling gait, and lower limb muscle weakness, and fatigue. Initial limb-girdle involvement was noted by neuro- and electromyographic findings (reduced duration, amplitude and interference pattern, and early recruitment of motor unit activation potentials at the deltoid and gluteus minimus muscles, bilaterally, with no anomalies of motor and sensory nerve conduction), in presence of normal muscle trophism as assessed by physical examination and MRI scan. Creatine phosphokinase was normal (56 IU/liter). The patient refused to undergo a muscle biopsy to investigate myopathic changes and the size of fibers. No cardiac involvement was recorded at this time. Bone turnover, as assessed by serum C-terminal telopeptide of type-1 collagen and serum bone alkaline phosphatase, was comparable with normal premenopausal controls. Similarly, no alterations were detected in the hypothalamus-hypophysis, -gonadal, -adrenal, and -thyroid axes. Lipid profile was normal (total serum cholesterol 4.34 mmol/liter, serum triglycerides 1.64 mmol/liter) with the exception of high-density lipoprotein cholesterol that was slightly low for the patient’s sex and age (0.85 mmol/liter). A standard oral glucose tolerance test was found to be normal (fasting glucose 4 mmol/liter; 2-h postchallenge glucose 5.55 mmol/liter), although plasma insulin levels were slightly elevated over the test (in particular, fasting and 2-h postchallenge values were 68.1 and 363.2 pM, respectively). Furthermore, measurement of insulin sensitivity by the glucose clamp technique showed a normal glucose uptake (33.0 µmol/kg/min, compared with 36.5 ± 2.3 µmol/kg·min of 10 lean normal subjects, mean ± SEM) under steady-state hyperinsulinemia (731 pM).

View larger version (106K): [in this window] [in a new window]   FIG. 1. Clinical features of MADA-het, compared with our MADA patient. She has a slightly pointed nose and micrognathia with no dental overcrowding (A). The hand x-ray evidences milder acroostelysis (C). The MRI scan shows a small intraabdominal (E), neck (G), and thigh (I) fat depot with a more represented sc panniculus. The corresponding clinical MADA features are represented in B, D, F, H, and J.

The coding exons of LMNA, including the splice junctions, were amplified by PCR and sequenced using CEQ 2000 (Beckman Coulter, Inc., Fullerton, CA).

Cell cultures

The MADA compound heterozygous (MADA-het) and control fibroblasts, obtained from skin biopsies, and HEK-293 cell lines were grown in DMEM supplemented with 10% fetal bovine serum and antibiotics (Euroclone Ltd., Wetherby, West York, UK). The written informed consents were obtained from the participants.

Western blot analysis

Sixty micrograms of protein extracted from the MADA-het cell culture were run on a 10% SDS-PAGE gel and transferred to nitrocellulose membrane. The membrane was probed with anti-lamin A/C (696) (Santa Cruz Biotechnology, Inc., Santa Cruz, CA; sc-7292) and anti-ß-actin (Santa Cruz sc-1616) as previously described (13).

Immunofluorescence staining

Human fibroblasts were analyzed with anti-heterochromatin protein-1ß (HP1ß) IgG (Mac 353), anti-trimethylated histone H3 Lys9 IgG, anti-lamin A/C (Santa Cruz, sc-6215) and anti-pre-lamin A (Santa Cruz, sc-6214) antibodies, as described earlier (13). Slides were mounted with a 4',6'-diamino-2-phenylindole-antifade reagent solution (Vector Laboratories, Burlingame, CA). Samples were observed with a fluorescence microscope (Nikon Corp., Tokyo, Japan) equipped with a charge-coupled device camera.

Electron microscopy

Fibroblasts were fixed with 2.5% glutaraldehyde-0.1 M phosphate, postfixed with 1% OsO₄ in a veronal buffer, dehydrated in an ethanol series, infiltrated with propylene oxide, and embedded in Epon resin. Ultrathin sections were stained with uranyl acetate-lead citrate and were observed with a Philips EM 400 transmission electron microscope, operated at 100 kV. A minimum of 200 nuclei per sample were observed.

Constructs and mutagenesis

The pcDNA 3.1 WT-LA vector was obtained from the cDNA of a healthy subject and using the primers sense 5'-AGGATCCATGGAGACCCCGTCCCAG-3' and antisense 5'-ACTCGAGCTGCCTGGCAGGTCCCAGA-3' containing the BamHI and XhoI restriction sites. The pcDNA 3.1 V440M-LA and the pcDNA 3.1 R527H-LA vectors were created by site directed mutagenesis using the following oligonucleotides: 440M, 5'-ACTAGCGGGCGCATGGCCGTGGAGGA-3' and 527H, 5'-GCGGGAACAGCCTGCATACGGCTCTC-3' (QuickChange II XL site direct mutagenesis kit; Stratagene, La Jolla, CA). The wild-type and the mutant pre-lamin A were sequenced.

Transient transfections

Cells were plated at approximately 500,000 cells per T25 flask. After 24 h, 1.0 x 10⁶ HEK 293 cells were transiently transfected with 5 µg of each construct using Nucleofector (Amaxa Biosystems, Cologne, Germany) under standard conditions. At 48 h after transient transfection, the transfected cells were stained with anti-lamin A/C and pre-lamin A antibodies as previously described.

	Results

Top Abstract Introduction Patient and Methods Results Discussion References

 
The affected subject (supplemental Fig. 1A, published as supplemental data on The Endocrine Society’s Journals Online Web site at http://jcem.endojournals.org), was a compound heterozygote for two missense mutations located in the C-terminal globular domain of the LMNA gene. The rare p.V440M (c.1318 GA) mutation is located in exon 7 and determines the substitution of valine with methionine (supplemental Fig. 1B). The c.1580 GA nucleotide transition, in exon 9, substitutes the arginine at codon 527 with histidine (CGTCAT) (supplemental Fig. 1C). All the analyzed intragenic single-nucleotide polymorphisms were found in a heterozygous state in the affected subject, confirming the absence of a large deletion. Each healthy parent was a simple heterozygote for one or the other mutation.

In patient cells, nuclear morphology alterations were found. In fact, irregularly shaped nuclei with large protrusions, intra/transnuclear membrane invaginations and doughnut-shaped nuclei were detected in approximately 30% of all cells (data not shown).

The pre-lamin A accumulation in MADA-het cells was localized at the nuclear rim and within membrane invaginations but was also found occasionally in intranuclear structures (Fig. 2, A and D). Control cells expressed a low amount of pre-lamin A, which was essentially distributed around the nuclear envelope (Fig. 2, A and D). The lamins A and C localization pattern remained largely unaltered in the patient’s nuclei, similar to the control fibroblasts (Fig. 2, B and D), accompanying blebs, protrusions, and membrane invaginations.

View larger version (48K): [in this window] [in a new window]   FIG. 2. A, Immunofluorescence staining of pre-lamin A in our patient’s fibroblasts (p.V440M/p.R527H) shows its accumulation in the nuclear rim and intranuclear structures. Pre-lamin A was undetectable in control fibroblasts. B, The lamins A and C localization pattern remains largely unaltered in the patient’s nuclei, similar to the control fibroblasts; the blebs also showed similar lamin A and C labeling. C, Double-indirect immunofluorescence staining of trimethylated histone H3 Lys9 and HP1ß shows an intranuclear clustered structure of these proteins in the patient’s nuclei, similar to the control. The DNA was counterstained with 4',6'-diamino-2-phenylindole. The merged image is also shown. D, Western blot analysis of LMNA products of whole cellular lysates from the control (C) MADA and compound heterozygous (MADA-het) cells. The proteins extracted from fibroblasts were subjected to a 10% SDS-PAGE, blotted, and then incubated using the anti-lamin A/C antibody. ß-Actin staining shows the same loaded. E, Electron microscopy analysis of MADA-het nuclei. Cultured control and MADA-het fibroblasts were fixed with 2.5% glutaraldehyde, included in epoxy resin, and ultrathin sections were examined by transmission electron microscopy. Heterochromatin detachment observed in MADA-het nuclei is indicated by arrowheads. Nuclear lamina thickening is indicated by an asterisk. The histogram shows the percentages of nuclear morphological defects (reported on the x-axis) in the control, MADA1 (13 ), and MADA-het fibroblasts. In the y-axis, the percentage of nuclei affected by morphological defects is indicated. Data are means ± SEM of three different observations. Statistical analysis was performed using the Student’s t test. The asterisk over the bars indicates statistically significant differences (P < 0.005) relative to each control. At least 200 nuclei/sample were counted.

The effects of each of the p.V440M and p.R527H mutations were investigated in transient transfection of HEK-293 cells. Overexpressed p.R527H lamin A determined an altered nuclear morphology and pre-lamin A accumulation. No significant nuclear anomalies and a low percentage of the pre-lamin A accumulation were observed in p.V440M transfected cells, compared with wild-type lamin A (supplemental Fig. 2).

	Discussion

Top Abstract Introduction Patient and Methods Results Discussion References

 
We present a case of apparent MADA compound heterozygous p.R527H/p.V440M.

The maternal p.R527H mutation cannot cause the clinical effects in the heterozygous state (10). However, nuclear dysmorphism has been occasionally noticed in healthy heterozygote subjects (10, 14).

The paternal p.V440M mutation has already been described in a compound heterozygous patient with the p.R482Q mutation, causing a severe familial partial lipodystrophy characterized by profound insulin resistance, diabetes and aggressive vascular disease (15). The p.V440M mutation alone was found in apparently healthy people (15), suggesting that this mutation may not act through a dominant negative mechanism as in the other mutations but might modulate the severity of the phenotype in a subject with another LMNA mutation as suggested by the present case.

Significant clinical heterogeneity associated with the change of a single amino acid has also been described for other laminopathies (4). Notably, the p. R527P gives rise to Emery-Dreifuss muscular dystrophy with signs of lipodystrophy (16, 17); the p.R527C/p.R471C genotype was found in a progeroid child with MAD features. This supports the notion that arginine 527 is within a key site for protein function.

Our patient showed a limb-girdle-like myopathy, which is never detected in MAD phenotypes. Lack of homozygosity for the p.R527H mutation probably attenuates the MADA phenotype, whereas the p.V440M mutation may contribute to both the muscle phenotype and the pathogenic effect of the single p.R527H mutation. The overexpression of p.R527H lamin A mimics the cellular MADA phenotype: accumulation of pre-lamin A in the nuclear rim and an alteration of the nuclear morphology (supplemental Fig. 2). On the other hand, the p.V440M expressed alone does not produce pre-lamin A and the mutated lamin A was localized uniformly in rounded nuclei. On a molecular level, we suggest that the presence of both p.R527H and p.V440M mutations in the C-terminal domain of the lamin proteins affect the structure of the nuclear lamina network more than in presence of one, independently. The pathogenic mechanism needs to be further investigated.

The MADA-het mild progeroid phenotype could be explained by light alterations in the distribution of heterochromatin proteins observed in her cells similar to the younger MADA ones (13). However, the marked reduction of peripheral heterochromatin areas in MADA-het fibroblasts, similar to homozygous MADA cells, indicates that the first effect of altered pre-lamin A processing is an overall disorganization of heterochromatin; this could lead to altered transcriptional activation of the nuclear domains involved.

The MADA-lipodystrophy is attributable to an adipocyte differentiation defect caused by anomalous interaction of pre-lamin A with the adipocyte transcription factor sterol regulatory element-binding protein-1 (18). Interestingly, the absence in our patient of metabolic alterations could reflect a partial normal adipocyte differentiation.

In conclusion, we present a case with an apparent MADA phenotype without clavicular hypoplasia, metabolic unbalances, and resembling limb-girdle myopathy. Interestingly, the lipodystrophic phenotype suggests that the lack of sc fat in LMNA-linked lipodystrophy is neither dependent nor causative of insulin resistance, which may in turn involve a different pathogenetic mechanism. Patients’ nuclei accumulate pre-lamin A analogously to the majority of progeroid laminopathies (6). The disorganization of the nuclear envelope confirms the crucial role of C-terminal domain of lamin A/C in the assembly of nuclear lamins. Our data support the extensive phenotypic heterogeneity of patients with LMNA mutations and confirm that complex laminopathic phenotypes with progeroid features are a consequence of profound heterochromatin disorganization. In addition, this report also suggests that the direct subsequent LMNA gene analysis in patients with myopathy of unknown causes could be considered.

	Acknowledgments

 
We are indebted to Professor V. Nigro (2nd University of Naples, Naples, Italy) for his help in sequencing the CAPN3 gene.

	Footnotes

 
This work was supported by Telethon Foundation (Italy), the Italian Ministry of Health, National Health Institute (Italy), EURO-Laminopathies (Contract LSHM-CT-2005-018690), and Istituto Superiore di Sanità, "Programma Italia-USA Malattie Rare" (Contract 526D/30).

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 11, 2007

Abbreviations: HP1ß, Heterochromatin protein-1ß; MADA, mandibuloacral dysplasia type A; MADA-het, MADA compound heterozygous; MRI, magnetic resonance imaging.

Received January 16, 2007.

Accepted August 30, 2007.

	References

Top Abstract Introduction Patient and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lombardi, F. Articles by Novelli, G. Search for Related Content PubMed PubMed Citation Articles by Lombardi, F. Articles by Novelli, G. Related Collections Metabolism