Dataset Information

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

ABSTRACT:

Purpose

To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder.

Methods

A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization.

Results

Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons.

Conclusion

Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.

SUBMITTER: Polla DL

PROVIDER: S-EPMC8725574 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

Polla Daniel L DL Farazi Fard Mohammad Ali MA Tabatabaei Zahra Z Habibzadeh Parham P Levchenko Olga A OA Nikuei Pooneh P Makrythanasis Periklis P Hussain Mureed M von Hardenberg Sandra S Zeinali Sirous S Fallah Mohammad-Sadegh MS Schuurs-Hoeijmakers Janneke H M JHM Shahzad Mohsin M Fatima Fareeha F Fatima Neelam N Kaat Laura Donker LD Bruggenwirth Hennie T HT Fleming Leah R LR Condie John J Ploski Rafal R Pollak Agnieszka A Pilch Jacek J Demina Nina A NA Chukhrova Alena L AL Sergeeva Vasilina S VS Venselaar Hanka H Masri Amira T AT Hamamy Hanan H Santoni Federico A FA Linda Katrin K Ahmed Zubair M ZM Nadif Kasri Nael N de Brouwer Arjan P M APM Bergmann Anke K AK Hethey Sven S Yavarian Majid M Ansar Muhammad M Riazuddin Saima S Riazuddin Sheikh S Silawi Mohammad M Ruggeri Gaia G Pirozzi Filomena F Eftekhar Ebrahim E Taghipour Sheshdeh Afsaneh A Bahramjahan Shima S Mirzaa Ghayda M GM Lavrov Alexander V AV Antonarakis Stylianos E SE Faghihi Mohammad Ali MA van Bokhoven Hans H

Genetics in medicine : official journal of the American College of Medical Genetics 20210406 7

<h4>Purpose</h4>To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder.<h4>Methods</h4>A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization.<h4>Results</h4>Biallelic variants in the TMEM222 gene were ident ...[more]

PMID: 33824500

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Project description:Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

Dataset Information

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

Purpose

Methods

Results

Conclusion

Publications

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

Similar Datasets

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