Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering

N Engl J Med. 2010 Feb 25;362(8):677-85. doi: 10.1056/NEJMoa0902630. Epub 2010 Feb 10.


Background: Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12.

Methods: We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America.

Results: We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms.

Conclusions: Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Chromosomes, Human, Pair 12*
  • Female
  • Frameshift Mutation
  • Genetic Linkage
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mannosephosphates / genetics
  • Mannosephosphates / metabolism
  • Metabolic Networks and Pathways / genetics
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Pakistan
  • Pedigree
  • Phosphoric Diester Hydrolases / genetics*
  • Sequence Analysis, DNA
  • Stuttering / genetics*
  • Transferases (Other Substituted Phosphate Groups) / genetics*


  • Mannosephosphates
  • mannose-6-phosphate
  • Transferases (Other Substituted Phosphate Groups)
  • GNPTAB protein, human
  • GNPTG protein, human
  • Phosphoric Diester Hydrolases
  • N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase