Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes

Raza, Muhammad Hashim; Domingues, Carlos E.F.; Webster, Ronald L.; Sainz, Eduardo; Paris, Emily; Rahn, Rachel M; Gutierrez, Joanne; Chow, Ho Ming; Mundorff, Jennifer; Kang, Chang Soo; Riaz, Naveeda; Basra, Muhammad Asim Raza; Khan, Shaheen N.; Riazuddin, Sheikh; Moretti-Ferreira, Danilo; Braun, Allen R.; Drayna, Dennis

doi:10.1038/ejhg.2015.154

Cited by 39 publications

(56 citation statements)

References 14 publications

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“…Recently, it was found that persistent developmental stuttering unaccompanied by other deficits or symptoms can be linked to mutations in the lysosomal enzyme-targeting pathway (LETP) [6]. Mutations in the LETP pathway account for 9-16% of all cases of persistent nonsyndromic stuttering[7]. …”

Section: Introductionmentioning

confidence: 99%

“…The mannose 6-phosphate is added to these acid hydrolases in a two-step process carried out by the products of three genes. Mutations in all three of these genes have been found in humans who stutter [6, 7]. However, the mechanisms by which mutations in an apparent “housekeeping gene” produce a deficit with the remarkable specificity of stuttering remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations

Barnes

Wozniak²,

Gutierrez

et al. 2016

Current Biology

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Summary A promising approach to understanding the mechanistic basis of speech is to study disorders that affect speech without compromising other cognitive or motor functions. Stuttering, also known as stammering, has been linked to mutations in the lysosomal enzyme-targeting pathway, but how this remarkably specific speech deficit arises from mutations in a family of general “cellular housekeeping” genes is unknown. To address this question, we asked whether a missense mutation associated with human stuttering causes vocal or other abnormalities in mice. We compared vocalizations from mice engineered to carry a mutation in the Gnptab (N-acetylglucosamine-1-phosphotransferase subunits alpha/beta) gene with wild type littermates. We found significant differences in the vocalizations of pups with the Gnptab stuttering mutation compared to littermate controls. Specifically, we found that mice with the mutation emitted fewer vocalizations per unit time, had longer pauses between vocalizations, and that the entropy of the temporal sequence was significantly reduced. Furthermore, Gnptab missense mice were similar to wild type mice on an extensive battery of non-vocal behaviors. We then used the same language-agnostic metrics for auditory signal analysis of human speech. We analyzed speech from people who stutter with mutations in this pathway and compared it to control speech, and found abnormalities similar to those found in the mouse vocalizations. These data show that mutations in the lysosomal enzyme targeting pathway produce highly specific effects in mouse pup vocalizations, and establish the mouse as an attractive model for studying this disorder.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations

Barnes

Wozniak²,

Gutierrez

et al. 2016

Current Biology

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“…Mutations in GNPTG result in an attenuated form of ML disease (mucolipidosis IIIgamma; MLIIIgamma) and, like the other genes within this pathway, have also been associated with persistent stuttering (2,11–15). The γ subunit contains an MRH (mannose-6-phosphate receptor homology) domain similar to those found in ER glucosidase II (16).…”

Section: Introductionmentioning

confidence: 99%

Enzyme-specific differences in mannose phosphorylation between GlcNAc-1-phosphotransferase αβ and γ subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology

Flanagan-Steet

Matheny

Petrey

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Targeting soluble acid hydrolases to lysosomes requires the addition of mannose 6-phosphate residues on their N-glycans. This process is initiated by GlcNAc-1-phosphotransferase, a multi-subunit enzyme encoded by the GNPTAB and GNPTG genes. The GNPTAB gene products (the α and β subunits) are responsible for recognition and catalysis of hydrolases whereas the GNPTG gene product (the γ subunit) enhances mannose phosphorylation of a subset of hydrolases. Here we identify and characterize a zebrafish gnptg insertional mutant and show that loss of the gamma subunit reduces mannose phosphorylation on a subset glycosidases but does not affect modification of several cathepsin proteases. We further show that glycosidases, but not cathepsins, are hypersecreted from gnptg−/− embryonic cells, as evidenced by reduced intracellular activity and increased circulating serum activity. The gnptg−/− embryos lack the gross morphological or craniofacial phenotypes shown in gnptab-deficient morphant embryos to result from altered cathepsin activity. Despite the lack of overt phenotypes, decreased fertilization and embryo survival were noted in mutants, suggesting that gnptg associated deposition of mannose 6-phosphate modified hydrolases into oocytes is important for early embryonic development. Collectively, these findings demonstrate that loss of the zebrafish GlcNAc-1-phosphotransferase γ subunit causes enzyme-specific effects on mannose phosphorylation. The finding that cathepsins are normally modified in gnptg−/− embryos is consistent with data from gnptab-deficient zebrafish suggesting these proteases are the key mediators of acute pathogenesis. This work also establishes a valuable new model that can be used to probe the functional relevance of GNPTG mutations in the context of a whole animal.

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“…Peripheral speech behaviors associated with stuttering are intermittent and range in expression from part-syllable repetitions and audible/ inaudible sound prolongations to inconsistencies during perceptually fluent speech (e.g., increased kinematic variability, reduced articulatory rate). Genetic predispositions may form the basis for stuttering and stuttering behaviors in at least a small subset of people who stutter (Kang et al, 2010;Raza et al, 2016); however, the factors that underlie stuttering within and across individuals are not well understood.…”

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confidence: 99%

The Impact of Social–Cognitive Stress on Speech Variability, Determinism, and Stability in Adults Who Do and Do Not Stutter

Jackson

Tiede

Beal

et al. 2016

J Speech Lang Hear Res

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,f,g Purpose: This study examined the impact of social-cognitive stress on sentence-level speech variability, determinism, and stability in adults who stutter (AWS) and adults who do not stutter (AWNS). We demonstrated that complementing the spatiotemporal index (STI) with recurrence quantification analysis (RQA) provides a novel approach to both assessing and interpreting speech variability in stuttering. Method: Twenty AWS and 21 AWNS repeated sentences in audience and nonaudience conditions while their lip movements were tracked. Across-sentence variability was assessed via the STI; within-sentence determinism and stability were assessed via RQA. Results: Compared with the AWNS, the AWS produced speech that was more variable across sentences and more deterministic and stable within sentences. Audience presence contributed to greater within-sentence determinism and stability in the AWS. A subset of AWS who were more susceptible to experiencing anxiety exhibited reduced across-sentence variability in the audience condition compared with the nonaudience condition.Conclusions: This study extends the assessment of speech variability in AWS and AWNS into the social-cognitive domain and demonstrates that the characterization of speech within sentences using RQA is complementary to the across-sentence STI measure. AWS seem to adopt a more restrictive, less flexible speaking approach in response to social-cognitive stress, which is presumably a strategy for maintaining observably fluent speech.

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Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes

Cited by 39 publications

References 14 publications

A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations

A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations

Enzyme-specific differences in mannose phosphorylation between GlcNAc-1-phosphotransferase αβ and γ subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology

The Impact of Social–Cognitive Stress on Speech Variability, Determinism, and Stability in Adults Who Do and Do Not Stutter

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