Molecular Genetics of Isolated Acromesomelic Dysplasia

Abstract

Acromesomelic dysplasia is a type of skeletal malformation affecting distal and middle segments of the extremities. Both isolated (nonsyndromic) and syndromic forms have been reported. In syndromic forms, it shows association with respiratory, cardiac, neurological and genital abnormalities. Acromesomelic dysplasia segregates in autosomal recessive mode of inheritance. Three genes ( , and ) have been reported to cause different forms of acromesomelic dysplasia.

Key Concepts

  • In case of AMDM, the short stature found in heterozygous carriers is probably caused by a codominant effect of the mutant allele.
  • Natriuretic peptides are hormones, involved in the regulation of various physiological processes.
  • Mutations in the NPR2 gene results in loss of functions and consequently affect the skeletal growth and is responsible for AMDM.
  • Mutations in GC‐binding domain in the gene Npr2 result in impaired endochondral ossification and severe dwarfism in mice.
  • The GDF5 is a ligand of BMP receptors, its absence results in abnormal joint formation and ligament defects.
  • AMDH patients are homozygous for a 22‐bp tandem duplication frameshift mutation in the mature region of CDMP‐1.
  • Du Pan dysplasia is caused by biallelic loss‐of‐function mutations in GDF5 gene.
  • Acrosomelic dysplasia Demirhan Type (AMDD) is caused by homozygous mutation in BMPR1B gene.
  • BMPR1B is the major receptor for GDF5, a signalling molecule of the BMP family that plays a major role in digit formation, joint development and chondrocyte differentiation.
  • Sheep with BMPR1B or BMP15 missense mutations do not exhibit a skeletal phenotype.
  • The skeletal and genital phenotype of the BmpR1b−/− mouse is similar to the clinical anomalies associated with the human BMPR1B mutation.

Keywords: acromesomelic dysplasia; clinical spectrum; GDF5; NPR2; BMPR1B; disease causing mutations

Figure 1. A typical acromesomelic patient showing short stature and short extremities (a). Affected members with AMDM showing short fingers and redundant skin (b). Bowing of forearm in acromesomelic patients (c).
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Khan, Saad U, Khan, Sher A, and Muhammad, Noor(Aug 2017) Molecular Genetics of Isolated Acromesomelic Dysplasia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027339]