What causes FKRP deficiency-associated congenital muscular dystrophy (MDDGA5)?

Updated: Jul 03, 2019
  • Author: Emad R Noor, MBChB; Chief Editor: Amy Kao, MD  more...
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Answer

This autosomal recessive disease was initially described in a patient with a mutation in the FKRP gene, which encodes a 55-kd ubiquitously expressed protein with high est c oncentrations in skeletal muscle, the heart, and the placenta. Since then, mutations in FKRP have been described in patients with Walker-Warburg syndrome, muscle-eye-brain disease, and limb-girdle muscular dystrophy type 2I.

Studies suggest that mutations in FKRP that cause severe phenotypes alter FKRP expression from the Golgi apparatus to the endoplasmic reticulum, whereas mutations that cause the milder limb-girdle muscular dystrophy type 2I phenotype do not. The authors hypothesized that glycosylation defects caused by mutations in FKRP may be due to the combined effects of loss of function and improper cellular targeting. Since the effects from individual mutations are likely complex and variable, this may explain the wide spectrum of phenotypes seen with FKRP mutations. [38]

FKRP is predicted to be a member of the O-glycosyltransferase or phosphosugartransferase family, but its exact role and enzymatic substrate have not been determined.

α-dystroglycan is abnormal in all patients with an FKRP mutation.

  • The most severely affected patients have a profound loss of α-dystroglycan.

  • Patients with a Duchenne-like phenotype have a moderate reduction.

  • Patients with a limb-girdle phenotype have only subtle alterations in α-dystroglycan immunostaining.


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