NDLI: A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay

Please wait, while we are loading the content...

A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay

Content Provider	Springer Nature Link
Author	Edvardson, Simon Elbaz Alon, Yael Jalas, Chaim Matlock, Ashanti Patel, Krishna Labbé, Katherine Shaag, Avraham Jackman, Jane E. Elpeleg, Orly
Copyright Year	2016
Abstract	Autosomal-recessive cerebellar atrophy is usually associated with inactivating mutations and early-onset presentation. The underlying molecular diagnosis suggests the involvement of neuronal survival pathways, but many mechanisms are still lacking and most patients elude genetic diagnosis. Using whole exome sequencing, we identified homozygous p.Val55Ala in the THG1L (tRNA-histidine guanylyltransferase 1 like) gene in three siblings who presented with cerebellar signs, developmental delay, dysarthria, and pyramidal signs and had cerebellar atrophy on brain MRI. THG1L protein was previously reported to participate in mitochondrial fusion via its interaction with MFN2. Abnormal mitochondrial fragmentation, including mitochondria accumulation around the nuclei and confinement of the mitochondrial network to the nuclear vicinity, was observed when patient fibroblasts were cultured in galactose containing medium. Culturing cells in galactose containing media promotes cellular respiration by oxidative phosphorylation and the action of the electron transport chain thus stimulating mitochondrial activity. The growth defect of the yeast thg1Δ strain was rescued by the expression of either yeast Thg1 or human THG1L; however, clear growth defect was observed following the expression of the human p.Val55Ala THG1L or the corresponding yeast mutant. A defect in the protein tRNAHis guanylyltransferase activity was excluded by the normal in vitro G−1 addition to either yeast tRNAHis or human mitochondrial tRNAHis in the presence of the THG1L mutation. We propose that homozygosity for the p.Val55Ala mutation in THG1L is the cause of the abnormal mitochondrial network in the patient fibroblasts, likely by interfering with THG1L activity towards MFN2. This may result in lack of mitochondria in the cerebellar Purkinje dendrites, with degeneration of Purkinje cell bodies and apoptosis of granule cells, as reported for MFN2 deficient mice.
Starting Page	219
Ending Page	225
Page Count	7
File Format	PDF
ISSN	13646745
Journal	Neurogenetics
Volume Number	17
Issue Number	4
e-ISSN	13646753
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2016-06-15
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Cerebellar atrophy Mitochondrial disorders Mitochondrial fusion Neurosciences Human Genetics Molecular Medicine
Content Type	Text
Resource Type	Article
Subject	Genetics Cellular and Molecular Neuroscience Genetics (clinical)

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene

Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency

PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy

Novel SIL1 mutations cause cerebellar ataxia and atrophy in a French-Canadian family

A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects

Erratum to: PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy

A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia

Homozygous KCNMA1 mutation as a cause of cerebellar atrophy, developmental delay and seizures

A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze family

A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay

Similar Documents

Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene

Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency

PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy

Novel SIL1 mutations cause cerebellar ataxia and atrophy in a French-Canadian family

A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects

Erratum to: PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy

A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia

Homozygous KCNMA1 mutation as a cause of cerebellar atrophy, developmental delay and seizures

A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze family

A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay