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Mandibuloacral dysplasia caused by homozygosity for the R527H mutation in lamin A/C
  1. J J Shen1,
  2. C A Brown2,
  3. J R Lupski1,3,
  4. L Potocki1
  1. 1Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA
  2. 2Molecular Diagnostics Laboratory, Fairview-University Medical Center, University of Minnesota, Minneapolis, Minnesota, USA
  3. 3Department of Pediatrics, Texas Children’s Hospital, Houston, Texas, USA
  1. Correspondence to:
 Dr L Potocki
 Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children’s Hospital, Clinical Care Center, 6621 Fannin, Suite 1560, Houston, Texas 77030, USA; lpotockibcm.tmc.edu

https://doi.org/10.1136/jmg.40.11.854

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    Lamins are intermediate filament proteins comprising a major structural component of the nuclear lamina, which underlies the inner membrane of the nuclear envelope in most somatic cells. In humans, seven alternatively spliced forms derive from three genes—LMNA, LMNB1, and LMNB2. Although their nuclear functions are currently being elucidated, it has been hypothesised that they are involved in membrane support, pore arrangement, envelope assembly, and chromatin organisation. Through these associations, the lamins may have more expanded roles at the cellular level and control diverse functions such as DNA synthesis, gene expression, and apoptosis.1–6

    Disorders caused by defects in the nuclear lamina associated proteins are referred to as the laminopathies. Thus far among the lamins, these have been described only for LMNA, which maps to chromosome 1q21.2 and encodes lamin A and lamin C through alternative splicing. A disparate group of seemingly unrelated diseases with different affected organ systems has been attributed to lamin A/C mutations. These include Charcot-Marie-Tooth disease type 2B,7 forms of dilated cardiomyopathy,8 both autosomal dominant and autosomal recessive forms of Emery-Dreifuss muscular dystrophy,9,10 limb girdle muscular dystrophy type 1B,11 Dunnigan-type familial partial lipodystrophy,12–14 and Hutchinson-Gilford progeria.15,16 Recently, Novelli et al categorised mandibuloacral dysplasia as a laminopathy resulting from lamin A/C mutation.17

    Mandibuloacral dysplasia (MAD; MIM 248370) is a rare autosomal recessive disorder. Affected individuals have a normal appearance at birth, then progressively develop lipodystrophy and dysmorphic craniofacial and skeletal features. Characteristic findings in MAD include mandibular hypoplasia, acro-osteolysis, prominent appearance of the eyes, dental overcrowding, beaked nose, delayed closure of the cranial sutures, clavicular dysplasia/osteolysis, joint contractures, and poikiloderma. Novelli et al analysed lamin A/C for mutations in five consanguineous Italian families with MAD.17 Homozygosity for a single mutation (R527H) …

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