Lombardi Francesca, Gullotta Francesca, Columbaro Marta, Filareto Antonio, D'Adamo Monica, Vielle Anne, Guglielmi Valeria, Nardone Anna Maria, Azzolini Valeria, Grosso Enrico, Lattanzi Giovanna, D'Apice Maria Rosaria, Masala Salvatore, Maraldi Nadir Mario, Sbraccia Paolo, Novelli Giuseppe
Department of Biopathology and Diagnostic Imaging, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
J Clin Endocrinol Metab. 2007 Nov;92(11):4467-71. doi: 10.1210/jc.2007-0116. Epub 2007 Sep 11.
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.
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.
The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated.
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.
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-1beta and histone H3 methylated at lysine 9.
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.
A型下颌骨发育不全症（MADA；OMIM 248370）是一种罕见的早老症综合征，其特征为颅面部和骨骼形态异常、脂肪营养不良以及代谢并发症。大多数意大利患者在编码核纤层蛋白A/C（核膜的中间丝成分）的LMNA基因的C末端尾部结构域中携带相同的纯合错义突变（p.R527H）。
本研究的目的是在具有其他知名患者中观察到的临床特征（鸟样面容、下颌骨和锁骨发育不全、肢端骨质溶解、脂肪营养不良、脱发）的个体中鉴定新的LMNA突变。
对LMNA基因进行测序。研究突变等位基因的功能特性。
我们报告了一名27岁的意大利女性，表现出类似MADA的表型。特征包括下颌骨发育不全、肢端骨质溶解、尖鼻、皮下脂肪部分缺失以及早老外观。由于没有锁骨发育异常且代谢指标正常，通常与肌肉无力和全身肌张力减退相关，这种表型可被视为非典型核纤层蛋白病。
我们鉴定出一名患者为p.R527H和p.V440M等位基因的复合杂合子。患者的细胞显示核形态异常、前体核纤层蛋白A积累以及核纤层厚度不规则。核纤层蛋白A和C显示正常表达和定位。电子显微镜检测到异染色质缺陷，其模式与其他核纤层蛋白病中观察到的相似。然而，染色质分析显示主要异染色质蛋白：异染色质蛋白-1β和赖氨酸9甲基化的组蛋白H3的分布模式正常。
该患者的临床和细胞特征显示出重叠的核纤层蛋白病表型，这可能是由于p.R527H和p.V440M等位基因的组合所致。
