Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation.
BACKGROUND
Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24).


OBJECTIVE
The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy.


METHODS
The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3-7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts.


RESULTS
LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase.


CONCLUSIONS
Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.
Agarwal
Anil K
AK
Division of Nutrition and Metabolic Diseases, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8537, USA.
Kazachkova
Irina
I
Ten
Svetlana
S
Garg
Abhimanyu
A
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution; D000886:Anthropometry; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D006228:Hand Deformities, Congenital / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood; D034904:Lamin Type A / Q000235:genetics*; D020738:Leptin / Q000097:blood; D008060:Lipodystrophy / Q000150:complications / Q000235:genetics*; D008334:Mandible / Q000002:abnormalities; D008856:Microscopy, Fluorescence; D009154:Mutation; D011371:Progeria / Q000150:complications / Q000235:genetics*; D012885:Skinfold Thickness
D007328:Insulin; C494847:LMNA protein, human; D034904:Lamin Type A; D020738:Leptin
J Clin Endocrinol Metab. 2005 Sep;90(9):5259-64
15998779
J Hum Genet. 2003;48(5):271-274
12768443
Cell Mol Life Sci. 2005 Nov;62(22):2669-78
16261260
Hum Mol Genet. 2005 Oct 15;14(20):2959-69
16126733
Am J Med Genet A. 2006 Dec 1;140(23):2603-24
16838330
J Med Genet. 2004 Aug;41(8):609-14
15286156
J Clin Endocrinol Metab. 2007 Nov;92(11):4467-71
17848409
J Investig Med. 2006 May;54(4):208-13
17152860
J Med Genet. 2005 Jun;42(6):e36
15937076
N Engl J Med. 2008 Feb 7;358(6):592-604
18256394
J Clin Endocrinol Metab. 2003 Jun;88(6):2821-4
12788894
Hum Mutat. 2006 Jun;27(6):524-31
16671095
Biochem Biophys Res Commun. 2007 Mar 30;355(1):78-84
17291448
Physiol Genomics. 2005 Oct 17;23(2):150-8
16046620
J Med Genet. 2003 Nov;40(11):854-7
14627682
Am J Med Genet A. 2007 Nov 1;143A(21):2598-603
17935239
J Biol Chem. 1993 Aug 5;268(22):16321-6
8344919
Aging Cell. 2007 Apr;6(2):139-53
17274801
J Clin Endocrinol Metab. 2002 Feb;87(2):776-85
11836320
Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12879-84
16129833
Mol Cell Biol. 2006 Jul;26(14):5360-72
16809772
J Clin Endocrinol Metab. 2005 Dec;90(12):6699-706
16174718
Int J Obes Relat Metab Disord. 1999 Mar;23(3):253-9
10193870
J Biol Chem. 2002 May 17;277(20):17381-4
11901143
Hum Mol Genet. 2003 Aug 15;12(16):1995-2001
12913070
Am J Hum Genet. 2002 Aug;71(2):426-31
12075506
Nat Med. 2008 Jul;14(7):767-72
18587406