(i) STU 29 family with c.3598G>A variant inGNPTAB gene
The fact that the highest linkage scores were obtained for this variant
combined with lack of other plausible genetic variant within the linkage
interval suggested increase risk of stuttering when present in either
one or two copies 19. Fedyna et
al., 27 reported 4/8 unrelated PWS carried atleast one
copy of p.Glu1200Lys mutation in GNPTAB gene and established this
as a founder mutation in Asian population, originating from Pakistan or
India. Recurrence of this lysine variant in heterozygous condition
(0.8%) that is segregating with affected status among our south Indian
stuttering family favors the founder effect in Asians.
Stuttering endophenotypes are homogenous and stable phenotypes. We
hypothesized that in a cohort with severe stuttering as an
endophenotype, there may be an increased chance to identify lysine
variants in homozygous condition. In order to verify this we tested
additionally, 26 severe PWS, but identified again only heterozygous
lysine variants in three of them; thereby increasing the overall
frequency of this variant to 4.4% (4/90*100) with an allele frequency
of 2.2% (4/180*100).
High frequency of this variant among south Asian ancestry (2.1%) in the
ExAC database, questions its pathogenicity. However, it is highly
conserved (Consurf = 8) and a mutation in it disrupts the helical
segment that may be crucial for interaction with other subunits or
proteins in lysosomal pathway (figure A4).
In a recent animal model study 3- to 8-day old mice pups were engineered
to carry two copies of the lysine mutation
(Gnptabmut/mut), resulting in significantly longer
pauses in their spontaneous vocalizations consistent with some features
of human stuttering, but was not found to be lethal as in case of
mutations reported in mucolipidosis. This was neither observed in
littermates without the mutation (Gnptabwt/wt) nor in
heterozygous (Gnptabmut/wt) littermates24. Though the causative role is well established for
the homozygous lysine variant in GNPTAB gene, the heterozygous
variants were similar to wild-type phenotypically in mouse model.
However it is still unclear how a recessive allele in heterozygous
condition is causing stuttering phenotype in human model; this trend has
been consistently observed not only in our study but in all other
reported studies19,21,28. This may be due to (i) a
second pathogenic mutation in this gene acting in trans or (ii)
other additive genetic factors that may play a causative role or (iii)
the gene may have a role in some other unknown pathway. Hence
identifying new interacting genes or pathways may clarify the causative
role of this gene in stuttering. In fact, dominance and recessiveness
are not essentially allelic properties but measured in relation to the
effects of other alleles at the same locus. Additionally, dominance may
change according to the level of organization of the phenotype and its
variations highlight the complexity of understanding genetic influences
on phenotypes29.
Two more GNPTAB homozygous mutations p.Ser321Gly and p.Ala455Ser
were engineered in mice, that also displayed vocalization deficits
traceable to abnormalities in astrocytes of corpus
callosum25.