A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease

Am J Hum Genet. 2001 Aug;69(2):420-7. doi: 10.1086/321290. Epub 2001 Jun 26.

Abstract

Menkes disease and occipital horn syndrome (OHS) are allelic, X-linked recessive copper-deficiency disorders resulting from mutations in ATP7A, or MNK. Classic Menkes disease has a severe phenotype, with death in early childhood, whereas OHS has a milder phenotype, with, mainly, connective-tissue abnormalities. Data suggest that steady-state localization of ATP7A to the trans-Golgi network (TGN) is necessary for proper activity of lysyl oxidase, which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity. Recently, it was reported that ATP7A-transcript levels as low as 2%-5% of normal are sufficient to result in the milder phenotype, OHS, rather than the phenotype of Menkes disease. In contrast to previously reported cases of OHS, we describe a case of OHS in which, because of a frameshift mutation, no normal ATP7A is produced. Although abundant levels of mutant transcript are present, there are substantially reduced levels of the truncated protein, which lacks the key dileucine motif L1487L1488. It has been demonstrated that the dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling between the TGN and the plasma membrane. The present report is the first to describe an ATP7A truncation that results in OHS rather than in Menkes disease. The data from the present report support the concepts that (1) OHS results from lower levels of functional ATP7A and (2) ATP7A does not require the dileucine motif to function in copper efflux.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics*
  • Adenosine Triphosphatases / metabolism
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Base Sequence
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cation Transport Proteins*
  • Child
  • Copper / deficiency
  • Copper / metabolism
  • Copper-Transporting ATPases
  • DNA Mutational Analysis
  • Deficiency Diseases / enzymology
  • Deficiency Diseases / genetics*
  • Deficiency Diseases / metabolism
  • Ehlers-Danlos Syndrome / enzymology
  • Ehlers-Danlos Syndrome / genetics*
  • Ehlers-Danlos Syndrome / metabolism
  • Exons / genetics*
  • Female
  • Fibroblasts
  • Frameshift Mutation / genetics*
  • Humans
  • Infant
  • Male
  • Menkes Kinky Hair Syndrome / enzymology
  • Menkes Kinky Hair Syndrome / genetics
  • Molecular Sequence Data
  • Occipital Bone
  • Pedigree
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • RNA Splice Sites / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Recombinant Fusion Proteins*

Substances

  • Carrier Proteins
  • Cation Transport Proteins
  • RNA Splice Sites
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Copper
  • Adenosine Triphosphatases
  • ATP7A protein, human
  • Copper-Transporting ATPases

Associated data

  • OMIM/304150
  • OMIM/309400