Genetic studies of stuttering are complicated by the high rate of spontaneous recovery in this disorder, especially among females,23
and by the likelihood of nongenetic and heterogeneous causes. These factors make it probable that unaffected persons can carry mutations associated with stuttering (i.e., may have nonpenetrant mutations) and that affected persons may not carry such mutations (i.e., may represent phenocopies). In addition, our findings in Family PKST72 are consistent with the possibility of assortative mating, in which preferential matings between affected persons or families can lead to stuttering caused by different mutant alleles within one large family. Three findings support a pathogenic role of these mutations in stuttering: only one of these GNPTAB
, and NAGPA
mutations was observed in the unaffected control subjects (i.e., in a single chromosome); all the mutations occurred at positions at which amino acid identity is conserved to a large extent across species; and all the mutations occurred within a single, well-defined metabolic pathway. Further supporting a causative role of these mutations in stuttering is the observation that although persons with mucolipidosis types II and III predominantly have skeletal, cardiac, and ocular disorders, they often have deficits in speech, particularly in expressive speech.24–26
These deficits have been viewed as secondary to the developmental delay that is typical in these disorders, but the sparing of some intellectual functions in mucolipidosis type III25
suggests that speech deficits may be primary rather than secondary in this disorder.
There may be several reasons why the mutations we identified in GNPTAB
result in stuttering rather than in mucolipidosis types II and III. First, mucolipidosis types II and III are generally believed to be autosomal recessive disorders, and all the unrelated affected persons in our sample, with two exceptions, were heterozygous and thus not expected to have either of these disorders. Another possibility is that all but one of the mutations we identified are missense rather than protein-truncation or deletion mutations, which are typically observed in mucolipidosis types II and III, and presumably have a more severe effect on protein function. None of the mutations we observed in GNPTAB
have been identified in persons with mucolipidosis type II or type III.27–30
No human disorder has yet been associated with mutations in NAGPA. This could be viewed as surprising, given that such mutations are predicted to have an effect on many different lysosomal enzymes. Our study suggests that a primary consequence of NAGPA mutation is nonsyndromic, persistent developmental stuttering.
An important reason to investigate stuttering is to better understand the neural structures and functions within the brain that generate human speech, which are poorly understood. Data regarding expression of these three genes in the human brain is limited. Data for the mouse brain are available for NAGPA
has the most localized expression in the brain, with high levels of expression in the hippocampus, hippocampal formation, and cerebellum (according to the Allen Brain Atlas31
). These structures are associated with, among other things, emotion and motor function. A person’s emotional state can exert a strong effect on the severity of stuttering. 1
In addition, whereas stuttering does not affect the ability to conceptualize words and sentences, it does affect the motor functions required for fluent speech. These three genes are widely expressed in many tissues in the body throughout life, and lifelong expression of these genes is consistent with the persistent nature of stuttering in our subjects.
We found NAGPA mutations only in persons of European descent, and these mutations occurred in 6 of the 270 affected North American–British subjects (2%). We observed mutations in GNPTAB and GNPTG in 15 of 393 affected persons who were of South Asian or European descent (4%). Persistent stuttering affects approximately 1% of the U.S. population, corresponding to about 3 million people, and an estimated 60 million people worldwide. Although our results can explain only a small fraction of cases of stuttering, these susceptibility variants are likely to be present in a large number of affected persons. Our findings also suggest that manifestations of mutations in these genes are not limited to the very small number of people who have frank symptoms of mucolipidosis type II or III. Rather, the manifestations of lysosomal targeting deficits may be present in a larger group of patients commonly encountered in medical practice.