A Novel Homozygous Ala529Val LMNA Mutation in Turkish Patients ...

0021-972X/05/$15.00/0 Printed in U.S.A.

The Journal of Clinical Endocrinology & Metabolism 90(9):5259 –5264 Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2004-2560

A Novel Homozygous Ala529Val LMNA Mutation in Turkish Patients with Mandibuloacral Dysplasia Abhimanyu Garg, Ozgur Cogulu, Ferda Ozkinay, Huseyin Onay, and Anil K. Agarwal 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 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.

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.1586C3 T; 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. (J Clin Endocrinol Metab 90: 5259 –5264, 2005)

Patients: Subjects were a male and a female patient with MAD who

M

ANDIBULOACRAL 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.1580G3 A 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). First Published Online July 5, 2005 Abbreviation: MAD, Mandibuloacral dysplasia. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

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 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.

5259

5260

J Clin Endocrinol Metab, September 2005, 90(9):5259 –5264

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. Physical examination revealed a height of 1.44 m (⬍3rd percentile) and a weight of 32 kg (⬍3rd percentile) and head circumference of 52 cm (⬍10th percentile). He had craniofacial anomalies such as prominent eyes (exophthalmous), prominent cheeks, small pinnae, beaked nose with hypoplastic alae nasi, and micrognathia with malalignment of teeth (Fig. 1B). He had narrow shoulders and thoracic cage. Hands revealed shortening of the distal phalanges. He had limited joint movements at the wrists, elbows, fingers, and toes. The skin was thin, and acanthosis nigricans was present in the axillae and neck. His pubertal development was normal. His testis volumes were 25 ml, and pubic hair was Tanner IV, but he had no axillary hair. 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 18to 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

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).

Garg et al. • Mandibuloacral Dysplasia and LMNA Mutation

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


5261

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

In the affected subjects from both the pedigrees, we found a homozygous c.1586 C3 T nucleotide transition in exon 9 of LMNA, which changes the 529 codon from GCT3 GTT 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 C3 T mutation using intragenic single-nucleotide polymorphisms (861T/C, IVS6⫹16G3A, 1338T3C, IVS8⫹44C3T, 1698C3T) 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

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.

5262


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. Immunofluorescence detection of lamin A/C in fibroblasts from very early, third or fourth, passages showed normal nuclear localization of lamin A in affected and unaffected subjects. About 50 –100 nuclei were observed. Only occasional abnormality such as nuclear bleb was seen in affected subjects (shown for MAD 1400.3; Fig. 3). In addition, staining for nuclear DNA in affected subjects revealed a honeycomb appearance (Fig. 3). Discussion

The clinical features of our patients of Turkish origin with homozygous Ala529Val LMNA mutation are compared with others presenting with MAD in Table 1. The phenotype of our patients are quite similar to those reported previously in MAD patients with homozygous Arg527His LMNA mutation (4, 6, 7). The onset of acroosteolysis occurred in both types of patients at about 4 yr of age. Joint contractures around elbow and wrists have been reported in both types of patients. All the patients had mandibular hypoplasia and clavicular resorption by 12–14 yr of age. Whether Ala529Val mutation is specifically associated with lack of breast development is intriguing (9). Such absence of breast development has not been reported in other female subjects with Arg527His LMNA mutation (6). For example, two female patients with MAD harboring homozygous Arg527His mutation reported by us had Tanner stage 4 and 5 breast development (3, 6). Unfortunately, at this time, only one female patient had the Ala529Val mutation, the other being a male.

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.


Thus, to confirm the association of the phenotype of lack of breast development with the Ala529Val genotype will require further evaluation of affected female subjects. Previously, we reported fasting serum triglyceride concentrations ranging from 1.34 –3.24 mmol/liter; high-density lipoprotein cholesterol concentrations of 0.97–1.35 mmol/ liter, and serum insulin values of 186 –258 pmol/liter in two female and one male with MAD and homozygous Arg527His LMNA mutation. Two of these patients also had postprandial hyperinsulinemia. Novelli et al. (4) also reported marked basal and postprandial hyperinsulinemia during the oral glucose tolerance test in all of their nine patients. Previously, other MAD patients (without genotype information) have been reported to have mild glucose intolerance, diabetes, and insulin resistance (15–17). In contrast, both the Turkish patients with MAD had normal serum triglycerides, insulin, and high-density lipoprotein cholesterol concentrations, suggesting a milder metabolic phenotype compared with those with Arg527His homozygous LMNA mutation (Table 1). Nonetheless, these patients had lipodystrophy and acanthosis nigricans as manifestations of insulin resistance. 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 –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 mu-



5263

TABLE 1. Comparison of clinical features of patients with MAD caused by LMNA or ZMPSTE24 mutations LMNA mutants R527H/R527H

A529V/A529V

K542N/K542Na

R527C/R471Cb

ZMPSTE24 mutants F361fsX379/W340R F361fsX379/N265Sc

References

Novelli et al. (4) Simha et al. (6) Shen et al. (7)

Current report

Plasilova et al. (18)

Cao and Hegele (22)

n (M/F) Reported age (yr) Age of onset of acroosteolysis (yr) Age at death (yr) Alopecia Premature graying of hair Loss of eyebrows/ eyelashes Lipodystrophy Open fontanelle Sexual maturation Mottled pigmentation Joint stiffness contractures Renal disease Calcified sc nodules Hyperinsulinemia Hypertriglyceridemia Low HDL cholesterol Nuclear morphological abnormalities in fibroblasts Other features

13 (7/6) d 1–36 4 –5

2 (1/1) 18, 21 4 –5

5 (2/3) 4 –17 1–2

1 (0/1) 28 2

Agarwal et al. (5) A. K. Agarwal et al. (unpublished observations) 2 (1/1) 24, 37 2

NA Subtotal in males No

NA No No

10, 16 Yes in both genders No

NA Yes NA

24, 37 No Yes

No

No

Yes

NA

No

Partial Yes Normal Yes Yes, elbows, shoulder, hips No No Yes, in almost all Variablee Variablee 10% of nuclei showed lobulationf

Partial Yes Normal Yes Yes

Generalized Yes (16) Delayed Yes Yes

NA NA Normal NA NA

Generalized Yes Normal Yes Yes

No No No No No Occasional nuclear bleb and honeycomb appearance

No No NA NA NA NA

No No NA NA NA NA

Yes Yes NA NA NA NA

Absent breast development in female

Premature loss of teeth

Severe osteoporosis and multiple fractures

Coronary and peripheral vascular disease

All patients have mandibular and clavicular hypoplasia and acroosteolysis. F, Female; HDL, high-density lipoprotein; M, male; NA, information not available. a Described by authors as Hutchinson-Gilford Progeria syndrome. b Described initially as Hutchinson-Gilford Progeria syndrome, but later the personal physician agreed with the diagnosis of MAD. c Agarwal, A. K., X. J. Zhou, R. K. Hall, K. Nicholls, A. Bankier, H. Van Esch, J.-P. Frynes, and A. Garg, (unpublished observation). d Personal communication from P. Sbraccia, Rome, Italy. e Data available on three patients. f Data on one patient (4).

tation 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 (25–27). 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. Received December 30, 2004. Accepted June 29, 2005. 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: [email protected]. This work was supported in part by the National Institutes of Health Grant R01-DK54387 and by the Southwestern Medical Foundation.

5264


References 1. Young LW, Radebaugh JF, Rubin P, Sensenbrenner JA, Fiorelli G, McKusick VA 1971 New syndrome manifested by mandibular hypoplasia, acroosteolysis, stiff joints and cutaneous atrophy (mandibuloacral dysplasia) in two unrelated boys. Birth Defects 7:291–297 2. Sensenbrenner JA, Fiorelli G 1971 New syndrome manifested by mandibular hypoplasia, acroosteolysis, stiff joints and cutaneous atrophy (mandibuloacral dysplasia) in two unrelated boys. In: Bergsma D, ed. The clinical delineation of birth defects: orofacial structures. Baltimore: Williams & Wilkins; 293–297 3. Simha V, Garg A 2002 Body fat distribution and metabolic derangements in patients with familial partial lipodystrophy associated with mandibuloacral dysplasia. J Clin Endocrinol Metab 87:776 –785 4. Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D’Apice MR, Massart C, Capon F, Sbraccia P, Federici M, Lauro R, Tudisco C, Pallotta R, Scarano G, Dallapiccola B, Merlini L, Bonne G 2002 Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 71:426 – 431 5. Agarwal AK, Fryns JP, Auchus RJ, Garg A 2003 Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 12:1995– 2001 6. Simha V, Agarwal AK, Oral EA, Fryns JP, Garg A 2003 Genetic and phenotypic heterogeneity in patients with mandibuloacral dysplasia-associated lipodystrophy. J Clin Endocrinol Metab 88:2821–2824 7. Shen JJ, Brown CA, Lupski JR, Potocki L 2003 Mandibuloacral dysplasia caused by homozygosity for the R527H mutation in lamin A/C. J Med Genet 40:854 – 857 8. Jackson AS, Pollock ML 1978 Generalized equations for predicting body density of men. Br J Nutr 40:497–504 9. Cogulu O, Gunduz C, Arkun R, Darcan S, Kadioglu B, Ozkinay F, Ozkinay C 2003 Mandibuloacral dysplasia with absent breast development. Am J Med Genet 119A:391–392 10. Jackson AS, Pollock ML, Ward A 1980 Generalized equations for predicting body density of women. Med Sci Sports Exerc 12:175–181 11. Lin F, Worman HJ 1993 Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J Biol Chem 268:16321–16326 12. Agarwal AK, Garg A 2002 A novel heterozygous mutation in peroxisome proliferator-activated receptor-␥ gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab 87:408 – 411 13. Dhe-Paganon S, Werner ED, Chi YI, Shoelson SE 2002 Structure of the globular tail of nuclear lamin. J Biol Chem 277:17381–17384 14. Krimm I, Ostlund C, Gilquin B, Couprie J, Hossenlopp P, Mornon JP, Bonne G, Courvalin JC, Worman HJ, Zinn-Justin S 2002 The Ig-like structure of the C-terminal domain of lamin A/C, mutated in muscular dystrophies, cardiomyopathy, and partial lipodystrophy. Structure (Camb) 10:811– 823 15. Freidenberg GR, Cutler DL, Jones MC, Hall B, Mier RJ, Culler F, Jones KL, Lozzio C, Kaufmann S 1992 Severe insulin resistance and diabetes mellitus in mandibuloacral dysplasia. Am J Dis Child 146:93–99


16. Welsh O 1975 Study of a family with a new progeroid syndrome. New York: Liss 17. Cutler DL, Kaufmann S, Freidenberg GR 1991 Insulin-resistant diabetes mellitus and hypermetabolism in mandibuloacral dysplasia: a newly recognized form of partial lipodystrophy. J Clin Endocrinol Metab 73:1056 –1061 18. Plasilova M, Chattopadhyay C, Pal P, Schaub NA, Buechner SA, Mueller H, Miny P, Ghosh A, Heinimann K 2004 Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome. J Med Genet 41:609 – 614 19. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Levy N 2003 Lamin A truncation in Hutchinson-Gilford progeria. Science 300:2055 20. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS 2003 Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298 21. Fukuchi K, Katsuya T, Sugimoto K, Kuremura M, Kim HD, Li L, Ogihara T 2004 LMNA mutation in a 45 year old Japanese subject with HutchinsonGilford progeria syndrome. J Med Genet 41:e67 22. Cao H, Hegele RA 2003 LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet 48:271–274 23. Boriani G, Gallina M, Merlini L, Bonne G, Toniolo D, Amati S, Biffi M, Martignani C, Frabetti L, Bonvicini M, Rapezzi C, Branzi A 2003 Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker implant, and heart failure in Emery-Dreifuss muscular dystrophy: a long-term longitudinal study. Stroke 34:901–908 24. Bonne G, Di Barletta MR, Varnous S, Becane HM, Hammouda EH, Merlini L, Muntoni F, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D, Schwartz K 1999 Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 21:285– 288 25. Raffaele di Barletta M, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, Romorini A, Voit T, Orstavik K, Merlini L, Trevisan C, Biancalana V, Housmanowa-Petrusewicz I, Bioine S, Ricotti R, Schwartz K, G B, Toniolo D 2000 Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Am J Hum Genet 66: 1407–1412 26. Sanna T, Dello Russo A, Toniolo D, Vytopil M, Pelargonio G, De Martino G, Ricci E, Silvestri G, Giglio V, Messano L, Zachara E, Bellocci F 2003 Cardiac features of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutations. Eur Heart J 24:2227–2236 27. Vytopil M, Benedetti S, Ricci E, Galluzzi G, Dello Russo A, Merlini L, Boriani G, Gallina M, Morandi L, Politano L, Moggio M, Chiveri L, Hausmanova-Petrusewicz I, Ricotti R, Vohanka S, Toman J, Toniolo D 2003 Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes. J Med Genet 40:e132

JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.