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A Novel Homozygous Ala529Val LMNA Mutation in Turkish Patients with Mandibuloacral Dysplasia

Division of Nutrition and Metabolic Diseases (A.K.A., A.G.), Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Faculty of Medicine, Department of Pediatrics (O.C., F.O., H.O.), Ege University, 35100 Bornova-Izmir, Turkey

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

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Mandibuloacral dysplasia (MAD) is a phenotypically heterogeneous, rare autosomal recessive disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, lipodystrophy, and mottled cutaneous pigmentation. MAD patients with type A lipodystrophy with loss of sc fat from the extremities and normal or slight excess in the neck and truncal regions have been previously reported to carry a homozygous Arg527His mutation in LMNA (Lamin A/C) gene. Among those with type B pattern of lipodystrophy with generalized loss of sc fat, we recently reported a patient carrying compound heterozygous mutations in an endoprotease, zinc metalloproteinase (ZMPSTE24), gene that is involved in posttranslational processing of prelamin A to mature lamin A.

Objective: Our objective was to carry out mutational analysis of LMNA in additional patients with MAD and type A lipodystrophy.

Design and Setting: We studied descriptive case reports at a referral center.

Patients: Subjects were a male and a female patient with MAD who belonged to two pedigrees from Turkey.

Main Outcome Measures: We assessed genotype-phenotype relationships.

Results: We now report that both these patients have a novel homozygous missense mutation (c.1586CT; c refers to cDNA reference sequence) in LMNA that replaces a well-conserved residue alanine at position 529 to valine. Intragenic single-nucleotide polymorphisms revealed a common haplotype spanning 2.5 kb around the mutated nucleotide in the parents of both the affected subjects, suggesting ancestral origin of the mutation. The female patient had no breast development despite normal menstruation, a phenotype different from that seen in women with MAD and Arg527His LMNA mutation.

Conclusions: We conclude that two homozygous missense LMNA mutations involving the arginine 527 and alanine 529 residues cause MAD with subtle variations in phenotype.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
MANDIBULOACRAL DYSPLASIA (MAD) (Mendelian Inheritance in Man no. 248370) is a rare autosomal recessive disorder, which presents with the following clinical features: postnatal growth retardation, craniofacial anomalies such as mandibular hypoplasia and bird-like facies, skeletal anomalies such as progressive osteolysis of the terminal phalanges and clavicles, and skin changes such as mottled hyperpigmentation and atrophy (1, 2). We identified two patterns of lipodystrophy in patients with MAD (3). Some patients had partial lipodystrophy (type A pattern) characterized by marked loss of sc fat from the extremities with normal or slight excess in the neck and truncal regions, whereas others had a more generalized loss of sc fat (type B pattern) involving the face, trunk, and extremities (3). Recently, a homozygous c.1580GA nucleotide transition (c refers to cDNA reference sequence; nucleotides are numbered starting from the first ATG codon) resulting in substitution of arginine 527 residue with histidine (Arg527His; the residues are numbered starting from the first codon from the N terminus of the protein) in the lamin A/C (LMNA) gene was reported in MAD patients with type A lipodystrophy (4). In another patient with MAD who presented with type B lipodystrophy, progeroid features, and sc calcified nodules, we reported compound heterozygous mutations in the zinc metalloproteinase (ZMPSTE24) gene (5).

So far, all 13 patients with MAD with a mutation in LMNA have been reported to have the same homozygous Arg527His missense mutation (4, 6, 7). Although all affected patients reported by Novelli et al. (4) were from consanguineous pedigrees from Italy and carried the same haplotype, suggesting a founder effect, other patients of Italian and Mexican origin reported by us (6) carried the same mutation on a distinct haplotype, suggesting that the mutations arose independently. These observations raised the possibility of association of the MAD phenotype with a highly specific genotype involving this exact amino acid substitution (7). However, we now report a novel homozygous Ala529Val mutation in LMNA in MAD patients belonging to two pedigrees from Turkey with subtle differences in phenotype compared with those with the Arg527His mutation.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
A written informed consent was obtained from all the participants, and the study protocol was approved by the Institutional Review Board of University of Texas Southwestern Medical Center and the Local Ethics Committee of Ege University, Izmir, Turkey.

Patient 1 (MAD 1300.4)

This 18-yr-old male of Turkish origin was referred to one of us (O.C.) for short stature, dysmorphic extremities and facial features. He was the second child of healthy consanguineous parents who were first cousins (Fig. 1A). The pregnancy was uneventful, and he was born full-term with a birth weight of 3.1 kg and a length of 50 cm. He had normal growth and development during the first 4 yr when he complained of joint stiffness and underdevelopment of the digits was noted.

View larger version (110K): [in this window] [in a new window]   FIG. 1. A, Pedigrees of patients with MAD. Affected individuals with homozygous Ala529Val mutation of LMNA gene are shown as filled black symbols, whereas heterozygous subjects are shown as half-filled symbols. The pedigree 1300 was consanguineous, and the parents of the affected subject were first cousins. Males are shown as squares and females as circles. The small dot indicates premature termination of pregnancy. B, Clinical features of patient 1300.4 at 18 yr of age showing pointed nose and micrognathia on the lateral view of the face. He had only a few hairs on the chin and upper lip. Hair on the eyebrows and eyelids were normal. C and D, Roentgenogram of the hand at age 14 yr reveals resorption of terminal phalanges consistent with acroosteolysis (C) and that of the chest reveals clavicular hypoplasia (D).

He had normal serum LH, FSH, testosterone, TSH, IGF-I, IGF-binding protein 3, free T₄, and cortisol. Serum alanine aminotransferase concentration was 10 U/liter, and aspartate aminotransferase was 23 U/liter (normal values, <40 U/liter for both). His serum glucose was 5.17 mmol/liter, cholesterol was 4.89 mmol/liter, triglycerides were 1.30 mmol/liter, high-density lipoprotein cholesterol was 1.45 mmol/liter, and low-density lipoprotein cholesterol was 2.33 mmol/liter. Oral glucose tolerance was normal. Fasting serum insulin concentration was 114 pmol/liter (normal range, 42–144 pmol/liter) and 120 min after oral glucose ingestion was 330 pmol/liter (normal range, 96–996 pmol/liter).

Skinfold thickness at various sites of the body were as follows: interscapular, 5.5 mm [less than the 10th percentile value of 8 mm for 18- to 55-yr-old men; data from Jackson and Pollock (8)]; triceps, 13 mm (10th to 90th percentiles for normal values, 6 mm and 23 mm, respectively); biceps, 3 mm (normal data not available); thigh, 7 mm (less than the 10th percentile value of 8 mm); and calf, 17 mm (normal data not available).

Roentgenological surveys at the age of 14 yr revealed mandibular and clavicular hypoplasia with acroosteolysis of distal phalanges (Fig. 1, C and D). His bone age was 14 yr according to Greulich Pyle standards. An electrocardiogram was normal, but echocardiography showed a 5-mm atrial septal defect. Abdominal ultrasonography and iv pyelography were normal. His karyotype was 46, XY.

Patient 2 (MAD1400.3)

The clinical features of this patient have been reported previously in brief when she was 14 yr old (9). This 21-yr-old lady of Turkish origin was the first child of healthy, unrelated parents (Fig. 1A). She had a healthy younger brother. Her mother’s first pregnancy terminated spontaneously at 10 wk of gestation. She was born full-term with a birth weight of 3.5 kg. She had normal growth and development during infancy and early childhood. The parents first noticed shortening and rounding of distal phalanges, swelling of all the phalangeal joints, underdevelopment of the chin, and malalignment of the teeth at the age of 5 yr. She attained menarche at age 10 yr and has had regular menstrual periods since. She presented with short stature, progressive deformity of the distal phalanges, and lack of breast development at the age of 13 yr.

Physical examination revealed a height of 1.37 m (<3rd percentile of Turkish children or 3.4 SD below the mean of normal children) and a weight of 33 kg (3rd to 10th percentile) and head circumference of 51.5 cm (2nd to 10th percentile). She had prominent eyes (exophthalmous), prominent cheeks, and a small and beaked nose with hypoplastic alae nasi, and mandibular hypoplasia with malaligned teeth. She had a broad neck with narrow shoulders and thoracic cage. The tips of the fingers and toes were rounded with marked resorption of all terminal phalanges. All the nails were hypoplastic, and interphalangeal joints were prominent. She had generalized joint stiffness with limitation of extension of both the wrists and elbows. The superficial veins were visible, and the skin was thin and atrophic with patchy mottled hyperpigmentation all over the body. Acanthosis nigricans was seen in the axillae and neck. The breast development was absent (Tanner stage 1), although the pubic and axillary hairs were normal. There was no alopecia or premature graying. Her triceps skinfold thickness was 11 mm (10th percentile value for women 18–55 yr old) (10) with subscapular skinfold thickness of 5 mm (less than the 10th percentile value of 7.5 mm). Her legs were muscular and showed prominent superficial sc veins.

Serum alanine aminotransferase was 14 U/liter, and aspartate aminotransferase was 24 U/liter (normal values, <40 U/liter for both). Her blood glucose concentration was 5.89 mmol/liter, total cholesterol was 4.29 mmol/liter, serum triglycerides were 0.12 mmol/liter, high-density lipoprotein cholesterol was 1.71 mmol/liter, and low-density lipoprotein cholesterol was 1.86 mmol/liter.

At the age of 14 yr, radiographic findings included mandibular and clavicular hypoplasia with acroosteolysis of distal phalanges. Anterior fontanel was fibrotic and open, and sagittal suture was palpable. Her bone age was 13 yr according to Greulich Pyle standards. Breast ultrasonography revealed absence of glandular breast tissue. As reported previously, serum levels of LH, FSH, prolactin, estradiol, TSH, and free T₄ were in the normal postpubertal range. IGF-I and IGF-binding protein 3, LHRH test, and estradiol level were found to be normal according to the pubertal stage. Oral glucose tolerance test was normal. Fasting serum insulin concentration was 78 pmol/liter (normal range, 42–144 pmol/liter) and 120 min after oral glucose ingestion was 492 pmol/liter (normal range, 96–996 pmol/liter). Her karyotype was 46, XX.

Mutational analysis of the LMNA gene

Genomic DNA was isolated from blood by using King Fisher (Thermo Labsystems, Marietta, OH) kit according to the manufacturer’s protocol. Direct sequencing of the entire coding region and the surrounding intron-exon boundaries of the LMNA gene was conducted in the probands from each pedigree. Primers that would amplify each exon of the lamin A/C gene from genomic DNA templates were designed from published sequence information (11). PCR was conducted as described earlier (12). For segregation analyses as well as for genotyping of intragenic single-nucleotide polymorphisms, only a few exons were sequenced in the family members. The PCR product was purified to remove primers and dNTPs and sequenced using ABI Prism 3100 (Perkin-Elmer Applied Biosystems, Foster City, CA). Structural modeling of Ig domain of the wild-type and mutant lamin A/C was performed according to the crystal structure determined by Dhe-Paganon et al. (13) and Krimm et al. (14).

Immunofluorescence microscopy

Fibroblasts were grown on coverslips and fixed for 20 min in methanol at –20 C. The cells were made permeable by incubating in 0.1% Triton X-100 for 15 min at room temperature and blocked for nonspecific binding by incubating them with 5% normal serum containing 0.3% BSA. The cells were incubated with antibody for lamin A, which recognizes both the forms, lamin A and C, (antibody H-110, at 1:100 dilution in blocking buffer; Santa Cruz Biotechnology, Santa Cruz, CA) for 60 min at 37 C. Primary antibody was removed, and the coverslip was washed with PBS and incubated with the secondary antibody conjugated with green fluorescent dye (Alexa fluor 488, diluted 1:100) and DNA staining dye TO-PRO-3 iodide (diluted 1:1000; Molecular Probes, Eugene, OR) for 60 min at 37 C. After washing, the coverslips were mounted using commercial mounting medium for fluorescent microscopy, Aqua Poly/Mount (Polysciences, Inc., Warrington, PA) and were examined using the Zeiss Axiovert 100M microscope.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
In the affected subjects from both the pedigrees, we found a homozygous c.1586 CT nucleotide transition in exon 9 of LMNA, which changes the 529 codon from GCTGTT resulting in substitution of alanine with valine. The mutation segregated in an autosomal recessive manner in these pedigrees. The parents were heterozygous for the mutation as were the siblings, and no heterozygote had the affected phenotype.

We determined haplotypes associated with the 1586 CT mutation using intragenic single-nucleotide polymorphisms (861T/C, IVS6+16GA, 1338TC, IVS8+44CT, 1698CT) extending 2.5 kb around the site of the mutation. The parents of the affected subjects from both the pedigrees carried the same haplotypes (T-G-T-C-C), indicating the ancestral origin of the mutation. However, there were no known common ancestors between the two families.

The alanine residue at position 529 is well conserved across many species, such as rat, mouse, chicken, and Xenopus laevis, suggesting that its substitution may be associated with the disease phenotype. In addition, there are only five known synonymous single-nucleotide polymorphisms in the exonic region of the LMNA gene, namely S17S, L204L, A287A, D446D, and H566H, and the A529V variant is not included as a polymorphism in the single-nucleotide polymorphisms database maintained by the National Center for Biotechnology Information. Prediction of the three-dimensional structure of the C-terminal Ig domain portion of lamin A shows that the arginine residue at position 527 forms a salt bridge with the glutamate residue at the 537 position (Fig. 2A). Substitution of arginine 527 to histidine interferes with the salt bridge formation (Fig. 2B). Interestingly, mutation of alanine at position 529 to valine can also interfere with the salt bridge formation between arginine 527 and glutamate 537 residues as shown in Fig. 2C.

View larger version (27K): [in this window] [in a new window]   FIG. 2. The ribbon diagrams of the structure of the C-terminal Ig domain portion of lamin A. A, Wild-type lamin A reveals salt bridge formation between the arginine residue at position 527 and glutamate residue at the 537 position. B, Substitution of arginine 527 to histidine in patients with MAD interferes with the salt bridge formation. C, Substitution of alanine at position 529 to valine may also interfere with the salt bridge formation between arginine 527 and glutamate 537 residues.

View larger version (34K): [in this window] [in a new window]   FIG. 3. Indirect immunofluorescence microscopy using lamin A/C antibody (H-110) in fibroblasts obtained from a control subject (A–C) and the patients MAD 1300.4 (D–F) and 1400.3 (G–I). A, D, and G, Immunostaining for lamin A/C; B, E, and H, nuclear DNA staining; C, F, and I, merged images from the lamin A/C and DNA staining. Very few nuclei were found to be abnormal in patients with MAD (note nuclear bleb in one of the nuclei in G, H, and I for patient MAD 1400.3). In both the patients, a honeycomb pattern of staining with nuclear DNA was observed in some nuclei.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

Recently, a consanguineous pedigree from India was reported with five affected subjects with Hutchinson-Gilford Progeria syndrome who carried a homozygous Lys542Asn mutation of LMNA (18). In contrast to the classical patients with Hutchinson-Gilford Progeria syndrome with heterozygous G608G or G608S mutation (19, 20, 21), all affected subjects from this Indian pedigree had severe mandibuloacral dysplasia with clavicular hypoplasia and onset of acro-osteolysis occurring at 1–2 yr of age (Table 1) (18). Unlike MAD patients with homozygous Arg527His and Ala529Val mutations, these patients showed features of progeria such as alopecia in both genders, loss of eyebrows and eyelashes, delayed sexual maturation, and early death. The patients were reported to have generalized lipodystrophy. Another 28-yr-old female with MAD has been described to have compound heterozygous mutations, Arg527Cys and Arg471Cys, in LMNA with alopecia, severe osteoporosis, and multiple fractures (22). In contrast to the clinical features of all patients with MAD as a result of LMNA mutations, patients with compound heterozygous mutations in the ZMPSTE24 gene develop renal disease during adulthood and sc calcified nodules in the phalanges and generalized lipodystrophy (5).

Interestingly, the two mutated residues in patients with MAD, arginine 527 and alanine 529, are in close proximity in the C-terminal globular domain of the protein and likely may be interacting with the same lamin A/C binding proteins (Fig. 2). Both these residues are well conserved through different species. Whether substitution of alanine 529 with valine results in MAD phenotype because of disruption of the salt bridge formation between arginine 527 and glutamate 537 or independently of the disruption of the tertiary structure remains unclear. It is likely that both the mutant forms of lamins A and C may be deficient in their interaction with chromatin or other nuclear lamina proteins and may induce similar phenotypes.

The unaffected members in our pedigrees who were heterozygous for the Ala529Val mutation revealed no phenotypic abnormalities suggestive of MAD. Similarly, parents and other siblings with heterozygous Arg527His LMNA mutation did not display any of the bone, cutaneous, or fat abnormalities seen in their homozygous offspring (4, 6). Interestingly, substitution of arginine 527 with proline is reportedly associated with autosomal dominant Emery-Dreifuss muscular dystrophy phenotype in the heterozygous subjects (23, 24). The substitution of adjacent residue threonine at position 528 with either lysine or arginine is also associated with Emery-Dreifuss muscular dystrophy (25, 26, 27).

Novelli et al. (4) reported lobulation of the nucleus with honeycomb staining of lamin A/C in 10% of the skin fibroblasts from an affected male with MAD and homozygous Arg527His mutation. In our patients, we were able to see only occasional nuclear dysmorphology such as a nuclear bleb in MAD 1400.3. Although we noted a honeycomb pattern of nuclear DNA staining in affected subjects, the significance of such a pattern remains unclear. However, our cells were from very early passages, and these observations cannot be directly compared with those reported by Novelli et al. (4) where passage number is not mentioned. It is possible that our patients may show more abnormalities in nuclear morphology as the cells age.

In summary, two affected patients with MAD were found to have homozygous Ala529Val mutation in the LMNA gene. Thus, MAD phenotype may result from two different homozygous LMNA mutations affecting nearby residues located in the carboxy terminal of the protein. The underlying molecular mechanisms by which various LMNA and ZMPSTE24 defects result in skeletal osteolysis and lipodystrophy remain to be elucidated.

	Acknowledgments

 
We are grateful to Ruth Giselle Huet and Meredith Millay for technical assistance and to Richard Auchus, M.D., Ph.D., for help with modeling of the lamin A crystal structure.

	Footnotes

 
This work was supported in part by the National Institutes of Health Grant R01-DK54387 and by the Southwestern Medical Foundation.

First Published Online July 5, 2005

Abbreviation: MAD, Mandibuloacral dysplasia.

Received December 30, 2004.

Accepted June 29, 2005.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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