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Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome
  1. M Plasilova1,*,
  2. C Chattopadhyay2,3,*,
  3. P Pal2,4,
  4. N A Schaub5,
  5. S A Buechner5,
  6. Hj Mueller1,
  7. P Miny1,
  8. A Ghosh2,
  9. K Heinimann1
  1. 1Research Group Human Genetics, Division of Medical Genetics, University Children’s Hospital and Department of Research, 4005 Basel, Switzerland
  2. 2Institute of Child Health, 11 Dr Biresh Guha Street, Calcutta 700017, India
  3. 3Calcutta Project Foundation, University of Basel, 4031 Basel, Switzerland
  4. 4S.B. Devi Charity Home, 6 Gulu Ostagar Lane, Calcutta 700006, India
  5. 5Department of Dermatology, University Clinics, 4031 Basel, Switzerland
  1. Correspondence to:
 Dr Ghosh
 Institute of Child Health, 11 Dr Biresh Guha Street, Calcutta 700017, India; apurbaghoshyahoo.com
 Dr Heinimann
 Research Group Human Genetics, Division of Medical Genetics, University Children’s Hospital, Roemergasse 8, 4005 Basel, Switzerland; karl.heinimannunibas.ch

https://doi.org/10.1136/jmg.2004.019661

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    Hutchinson-Gilford progeria syndrome (HGPS; MIM 176670) is an extremely rare genetic disorder displaying features reminiscent of premature senescence.1,2 Typically, affected children appear normal at birth, but begin to develop characteristic symptoms within the first years of life such as failure to thrive, alopecia, lipodystrophy, and scleroderma-like skin changes. Though the first HGPS cases were described more than 100 years ago,1,3 its extreme rarity (1:4–8 000 000) and mostly sporadic occurrence made it difficult to identify the underlying genetic cause. By means of homozygosity mapping as well as candidate gene analysis, two research groups recently reported that heterozygous, recurrent de novo point mutations in the lamin A/C gene (LMNA; MIM 150330), a component of the filamentous meshwork of the nuclear lamina, caused HGPS.4,5

    LMNA encodes two A-type lamins, lamin A and C, which are the result of alternative splicing and share the first 566 amino acids.6,7 Together with B-type lamins, they represent the main components of the nuclear lamina. In contrast to B-type lamins, which are ubiquitously expressed in all cell types at all developmental stages, A-type lamins are absent in the cells of the early embryo, embryonic stem cells, stem cells of the immune and haematopoietic systems as well as in cells of the neuroendocrine system (reviewed in Goldman et al8 and Mounkes et al9).

    Besides HGPS, germline mutations in LMNA have been shown to cause seven phenotypically different disorders, inherited in an autosomal dominant and/or recessive manner.4,5,10 Considering the tissue(s) affected, they can be grouped into those involving mainly (i) striated and cardiac muscle, (ii) peripheral nerves, and (iii) white adipose tissue and bones.9 Together with HGPS, two of them belong to the so-called progeroid syndromes: an atypical form of Werner syndrome (WRN; …

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    Footnotes

    • ↵* Dr Plasilova and Dr Chattopadhyay equally contributed to this article.

    • This work was supported in part by grants from the Swiss Foundation for Nutrition Research and the Swiss National Science Foundation.

    • Conflict of interest: none declared.