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A Homozygous Mutation in the Lamin A/C Gene Associated with a Novel Syndrome of Arthropathy, Tendinous Calcinosis, and Progeroid Features

Center for Human Genetics (H.V.E., J.-P.F.) and Department of Orthopedics (P.D.), University Hospital of Leuven, B-3000 Leuven, Belgium; and Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and Center for Human Nutrition, University of Texas Southwestern Medical Center (A.K.A., A.G.), Dallas, Texas 75390

Address all correspondence and requests for reprints to: Abhimanyu Garg, Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: Abhimanyu.garg{at}utsouthwestern.edu.

	Abstract

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Context: Mutations in the lamin A/C (LMNA) gene have been reported in a wide variety of disorders, including lipodystrophies, cardiomyopathy, muscular dystrophies, neuropathy, mandibuloacral dysplasia, restrictive dermopathy, and progeria.

Objective: The objective of this study was to carry out mutational analysis of LMNA in a patient with a novel syndrome of arthropathy, tendinous calcinosis, and progeroid features.

Design: The study design was a descriptive case report.

Setting: The study was performed at a referral center.

Patient: A 44-yr-old male of European descent with an autosomal recessive arthropathy syndrome affecting predominantly the distal femora and proximal tibia in the knee with tendinous calcifications was studied. He also had progeroid features, such as pinched nose and micrognathia, cataract, alopecia, generalized lipodystrophy, and sclerodermatous skin.

Main Outcome Measures: The main outcome measures were mutational analysis of lamin A/C (LMNA) and its processing enzyme, zinc metalloproteinase (ZMPSTE24), as candidate genes.

Results: We found a homozygous nucleotide substitution, 1718C>T, in exon 11 of the LMNA gene, resulting in substitution of a well-conserved residue serine at position 573 with leucine (S573L). This missense mutation only affects lamin A, not lamin C, because the alternative splicing site is located in exon 10. Immunofluorescence staining of the nuclei from his skin fibroblasts showed occasional misshapen morphology.

Conclusions: The S573L homozygous LMNA mutation is associated with a novel phenotype of arthropathy, tendinous calcifications, and progeroid features distinct from the acroosteolysis previously reported in patients with mandibuloacral dysplasia caused by LMNA or ZMPSTE24 mutations. Thus, arthropathy with tendinous calcifications can be added to the growing list of disorders associated with LMNA mutations.

	Introduction

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MUTATIONS IN THE lamin A/C (LMNA) gene have been reported to cause many diverse autosomal dominant or recessive syndromes (1, 2). The autosomal dominant syndromes include familial partial lipodystrophy of the Dunnigan type, cardiomyopathy, Emery-Dreifuss and limb-girdle muscular dystrophies, and restrictive dermopathy (1, 2, 3). De novo heterozygous LMNA mutations have also been noted in disorders such as Hutchinson-Gilford progeria syndrome and atypical Werner syndrome (1, 2). The autosomal recessive syndromes due to LMNA mutations include mandibuloacral dysplasia, Charcot-Marie tooth neuropathy, and congenital muscular dystrophy (1, 2). We report a novel autosomal recessive syndrome in a 44-yr-old patient with arthropathy predominantly affecting the femoral and tibial bones in the knee joints associated with tendinous calcifications and progeroid features who had a distinct homozygous missense mutation, 1718C>T (S573L), in the LMNA gene.

	Patient and Methods

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The protocol was approved by the appropriate institutional review board of University of Texas Southwestern Medical Center (Dallas, TX) and University Hospital of Leuven (Leuven, Belgium). All the subjects gave written informed consent.

Patient

This 44-yr-old male from Luxemburg was born to healthy unrelated parents (Figs. 1A and 2A). He first presented with progressive complaints of pain in both knees at the age of 30 yr, when degenerative changes in both knees were noted. At the age of 34 yr, he was operated on for a unilateral posterior capsulated cataract of the left eye. The right eye was normal. At age 35 yr, he developed a chronic ulcer on his right elbow, and examination revealed sclerotic and atrophic skin, especially affecting his extremities, which suggested the diagnosis of progeria/early aging syndrome. Roentgenological survey at that time revealed diffuse osteoporosis and calcifications of the tendons at the knees, elbows, and ankles, with further progression of degenerative changes in the knees (Fig. 1, B–E). There was no evidence of diabetes, hypogonadism, or neurological disorder. At the age of 38 yr, he underwent right total knee replacement, but 2 months later, the prosthesis had to be removed due to septic arthritis. Preoperative evaluation revealed normal electrocardiogram and no evidence of hypertension or cardiomegaly on chest roentgenogram. At the age of 43 yr, progeroid facies with small pinched nose, small mandible, small lips, and crowded teeth in the mandible were noted. His height was 1.63 m, weight was 64 kg, and body mass index was 24.1 kg/m². He had generalized lipodystrophy affecting his arms, legs, and trunk. His skin was dry and atrophic, and he had a nonhealing wound on the left medial malleolus. He had only sparse hair on the scalp, eyelids, and eyebrows. He had limited mobility of the knees, elbows, and ankle joints.

View larger version (113K): [in this window] [in a new window]   FIG. 1. A, Frontal view of the patient at age 43 yr, showing loss of hair on the forehead and eyebrows, pinched nose, and small mandible. B–E, Lateral and anterior-posterior roentgenograms of the right (B and D, respectively) and left (C and E, respectively) knees. The right knee is status post joint replacement surgery, with removal of the prosthesis due to infection. Both knees show superior displacement of the patella (more marked in the right knee) with calcifications of the quadriceps tendon anterior to the patella. The left knee shows reduction in joint space with loss of articular cartilage and erosion of the femoral medial condyle and proximal tibia particularly on the medial side, resulting in varus deformity. A bone spur is seen on the lateral femoral condyle. F, Antero-posterior view of the chest, showing normal clavicles without any clavicular resorption. G, Antero-posterior view of the hand, showing lack of acroosteolysis. H, Lateral view of the left elbow, showing calcification of the soft tissues on the dorsal side, most likely in the triceps tendon. I and J, Lateral (I) and antero-posterior (J) views of the left foot reveal calcifications of the Achilles tendon as well as on the medial malleolus, and at the first metatarso-phalangeal and the second proximal inter-phalangeal joints. There was no evidence of acroosteolysis.

View larger version (19K): [in this window] [in a new window]   FIG. 2. A, Pedigree of the patient. The proband is shown as filled black symbol with an inclined arrowhead. His son, a genetically confirmed heterozygote, is shown as a half-filled symbol, and the parents, who were obligate heterozygotes, are shown as half-filled shaded symbols. Males are represented as squares, and females as circles. B, Sequence chromatogram of the patient (II-2), showing homozygous substitution of nucleotide 1718C to T in exon 11 of the LMNA gene, resulting in Ser573Leu substitution (S573L).

The patient had elevated values of serum alkaline phosphatase (440 U/liter; normal, <270 U/liter), aspartate aminotransferase (118 U/liter; normal, <38 U/liter), alanine aminotransferase (135 U/liter; normal, <41 U/liter), -glutamyltransferase (527 U/liter; normal, <53 U/liter), and total bilirubin (2.0 mg/dl; normal, <1.0 mg/dl). He also had high plasma uric acid levels (8.4 mg/dl; normal range, 3.5–7.2 mg/dl). A random plasma glucose concentration was 11.8 mmol/liter (normal, <11.1 mmol/liter). He also had dyslipidemia with a serum cholesterol concentration of 6.52 mmol/liter, a serum triglyceride concentration of 4.47 mmol/liter, and a high-density lipoprotein cholesterol concentration of 0.85 mmol/liter. Urinalysis revealed mild proteinuria; however, the urinary protein/creatinine ratio was 0.19 g/g creatinine (normal range, 0–0.25 g/g creatinine). Serum creatinine was also normal. His karyotype was normal.

A skeletal survey revealed osteopenia of the hands, shoulder joints, and pelvic bones. He had hyperostosis frontalis. There was no evidence of acroosteolysis or clavicular resorption. The right knee revealed osteopenia and alterations consistent with status post removal of infected prosthesis (Fig. 1, B and D). Both knees showed superior displacement of the patella (more marked in the right knee) with calcifications of the quadriceps tendon anterior to the patella. The left knee showed a reduction in joint space with loss of articular cartilage and erosion of the femoral medial condyle and proximal tibia, particularly on the medial side, resulting in varus deformity (Fig. 1, C and E). A bone spur was seen on the lateral femoral condyle. He had tendinous calcification posterior to the left elbow joint as well as at the medial epicondyle (Fig. 1H). He had mild lumbar dextro-convex scoliosis, but no vertebral anomalies. Soft tissue calcifications of the Achilles tendon, around the medial malleolus and the first metatarso-phalangeal and the second proximal interphalangeal joints, were seen on the left foot (Fig. 1, I and J). The patient died at the age of 44 yr of Staphylococcus aureus sepsis resulting from infection of his skin ulcers. An autopsy was not performed.

Mutational analysis

Genomic DNA was isolated from the blood sample, and the exons and splice-site junctions of LMNA and ZMPSTE24 genes were amplified as described previously (4). The PCR product was purified and sequenced using ABI PRISM 3100 (Applied Biosystems, Foster City, CA). Sequences were compared using Vector NTi Suite 6 software (InforMax, Inc., Bethesda, MD) and by visual inspection.

Immunofluorescence staining

Fibroblasts from the affected subject, from 10–12 passages, and from an unrelated control subject were grown on coverslips and fixed in cold (–20 C) methanol for 20 min. The cells were made permeable by incubation in 0.1% Triton X-100 for 15 min at room temperature and were blocked for nonspecific binding by incubation with 5% normal serum containing 0.3% BSA. The cells were incubated with antibody recognizing N-terminus of both lamins A and C (H-110 at a dilution of 1:100 in blocking buffer; Santa Cruz Biotechnology, Inc., Santa Cruz, CA.). Lamin B1 was recognized by mouse monoclonal antibody (clone 2X89 at a 1:100 dilution; U.S. Biological, Swampscott, MA) by incubation for 60 min at 37 C. Primary antibodies were removed, and the coverslips were washed with PBS and incubated with the secondary antibodies (goat antimouse Alexa 488 for lamin B1, and goat antirabbit Alexa 568 for lamin A/C at a 1:400 dilution; Molecular Probes, Eugene, OR). After washing, the cells were stained with 4',6-diamido-2-phenylindole hydrochloride for 60 sec, rewashed, and mounted using Aqua Poly/Mount mounting medium for fluorescent microscopy (Polysciences, Inc., Warrington, PA). Deconvolution microscopy was performed using -vision microscope (Applied Precision, Issaquah, WA).

	Results

Top Abstract Introduction Patient and Methods Results Discussion References

 
The patient had a homozygous mutation, 1718C>T, in exon 11 of the LMNA gene, resulting in Ser573Leu substitution (S573L; Fig. 2B). The patient did not reveal any mutation in the ZMPSTE24 gene. His son was heterozygous for the S573L mutation in LMNA. Alignment of this region shows that the serine residue at position 573 is well conserved across species such as the mouse, rat, chicken, and Xenopus (5).

Because the mutation is in the C-terminal region, which undergoes posttranslational processing involving farnesylation and carboxymethylation of the CAAX motif and proteolytic cleavages involving ZMPSTE24, we determined whether there was any prelamin A accumulation in the protein extracted from the fibroblasts. The Western blot did not reveal any prelamin A accumulation (data not shown). RNA analysis of the patient’s skin fibroblasts did not reveal any abnormal transcripts, suggesting that this mutation does not activate any cryptic splice site (data not shown).

Microscopic examination of nuclei from skin fibroblasts of the affected subject showed occasional (<10%) misshapen nuclei, such as bilobed nuclei, which were not seen in fibroblasts from the normal control (Fig. 3). These nuclear abnormalities did not affect the localization of lamin A/C or B1.

View larger version (26K): [in this window] [in a new window]   FIG. 3. Double immunofluorescence detection of nuclear lamina proteins, lamin A/C and B1, from skin fibroblasts. Shown are the single z-slice for nuclear localization of lamin A/C (A), lamin B1 (B), and DNA stain (C) and the colocalization (D) in an unrelated control subject. Corresponding images from the affected patient show normal-appearing nuclei (E–H) as well as an abnormal bilobed nucleus (I–L). Deconvoluted images (magnification, x60) were obtained and processed using IMARIS image processing software (Bitplane, Inc., St. Paul, MN).

	Discussion

Top Abstract Introduction Patient and Methods Results Discussion References

We detected a homozygous missense mutation, S573L, in LMNA. His son, who was heterozygous for the S573L mutation, had no arthropathy, premature aging, or lipodystrophy. The S573L variant was excluded to be a polymorphism on analysis of 450 chromosomes (5). This mutation in exon 11 of the LMNA gene is unique to lamin A and does not affect lamin C, because the alternative splicing site for lamin C mRNA formation is located in exon 10. Very few other heterozygous missense mutations affecting only lamin A have been reported in patients with variable phenotypes. For example, R582H and R584H were associated with atypical familial partial lipodystrophy of the Dunnigan variety (6, 7), R644C with cardiomyopathy (5), R624H (in a compound heterozygote with E358K) with Emery-Dreifuss muscular dystrophy (8), and G608G and G608S mutations with Hutchinson-Gilford progeria syndrome (9, 10, 11). These laminopathies, due to mutations observed only in lamin A, affect multiple tissues, such as the adipose, cardiac, cutaneous, nervous, and skeletal tissues, which also suggests a more important role for lamin A than lamin C in providing structural integrity to nuclear architecture.

Serine 573 is located beyond the Ig-like domain, which is between residues 436 and 544. This would suggest that substitution of serine 573 with a bulkier and hydrophobic residue leucine is not well tolerated in the region. Moreover, the high conservation of serine 573 across species suggests its functional role in lamin A protein and increases the likelihood that its substitution is associated with the disease phenotype.

Interestingly, the S573L heterozygous mutation in LMNA has recently been reported in two Italian sisters; the younger one (50 yr old) featured an isolated dilated cardiomyopathy, whereas the older one (60 yr old) was totally asymptomatic (5). However, the mother of our patient, obligate heterozygote for the S573L mutation, reportedly did not have any cardiac problems and neither did his 15-yr-old son. Our patient also did not have any evidence of cardiomyopathy. Thus, the association of heterozygous S573L mutation with a cardiac phenotype remains unclear.

Our patient did have some overlapping features of progeroid syndromes, such as alopecia, pinched nose, small mandible, atrophic skin, cataract, and lipodystrophy. He also had metabolic complications, such as hypertriglyceridemia, low high-density lipoprotein cholesterol, possibly mild diabetes, and hyperuricemia. Abnormal liver function tests most likely were related to his excessive alcohol consumption, but could be related to other metabolic abnormalities as well. Some of these features are seen in patients with Hutchinson-Gilford progeria syndrome and mandibulo-acral dysplasia (9, 11, 12). However, he did not have acral osteolysis involving the phalanges and the clavicles, which has been reported in all patients with mandibuloacral dysplasia who had either homozygous R527H or K542N mutations or compound heterozygous R527H/R471C mutations (10, 12, 13, 14, 15, 16). To our knowledge, none of the patients with mandibuloacral dysplasia due to LMNA mutations has developed degenerative changes in the distal femur and proximal tibia (10, 12, 13, 14, 15, 16). Furthermore, our patient had cataract and tendinous calcinosis, which have not been reported in mandibuloacral dysplasia patients (10, 12, 13, 14, 15, 16). Interestingly, sc calcification with nodule formation was present in another patient with mandibuloacral dysplasia who had ZMPSTE24 mutations (4). Thus, our patient, who has a homozygous S573L LMNA mutation, has a unique phenotype, not reported previously.

How mutations in lamin A/C protein result in so many different disease phenotypes remains poorly understood. Several hypotheses have been advanced, including mechanical shearing and differential gene regulation by interaction with nuclear chromatin (2, 17, 18). Another possibility could be that there is an abnormal interaction between mutant lamin A and other nuclear lamina proteins. The carboxyl-terminal region of lamin A (residues 536–646) has been shown to bind to actin protein, another element of nuclear skeleton (19). The mutant S573L lamin A could result in complete dissociation of lamin A and actin interaction or may have reduced affinity for actin, resulting in premature apoptosis (20).

	Acknowledgments

 
We thank Geral Dietz, M.D. (Department of Radiology, University of Texas Southwestern Medical Center), for help with interpretation of the roentgenograms; Kate Luby-Phelps and Abhijit Bugde (Cell Imaging Core Facility, University of Texas Southwestern Medical Center) for help with acquiring the images; and Ruth Giselle Huet, Jennifer Sprayberry, and Meredith Millay for management of DNA and patient databases, illustrations, and technical assistance.

	Footnotes

 
This work was supported in part by National Institutes of Health Grant R01-DK-54387 and the Southwestern Medical Foundation. H.V.E. and P.D. were supported by the Fund for Scientific Research-Flanders, Belgium (Fonds voor Wetenschappelijk Onderzoek-Vlaanderen).

First Published Online November 8, 2005

¹ H.V.E. and A.K.A. contributed equally to this study.

Received June 10, 2005.

Accepted October 27, 2005.

	References

Top Abstract Introduction Patient and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: 91/2/517    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart 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 Van Esch, H. Articles by Garg, A. Search for Related Content PubMed PubMed Citation Articles by Van Esch, H. Articles by Garg, A. Related Collections Calcium and Bone Metabolism Metabolism