Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Woldegebriel, Rosa; Kvist, Jouni; Andersson, Noora; Õunap, Katrin; Reinson, Karit; Wojcik, Monica H.; Bijlsma, Emilia K.; Hoffer, Mariëtte J.V.; Ryan, Monique M.; Stark, Zornitza; Walsh, Maie; Cuppen, Inge; Boogaard, Marie‐José H. van den; Bharucha‐Goebel, Diana; Donkervoort, Sandra; Winchester, Sara; Zori, Roberto T.; Bönnemann, Carsten G.; Maroofian, Reza; O’Connor, Emer; Houlden, Henry; Zhao, Fen; Carpén, Olli; White, Matthew A.; Sreedharan, Jemeen; Stewart, Murray; Ylikallio, Emil; Tyynismaa, Henna

doi:10.1093/hmg/ddaa051

Cited by 7 publications

(11 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As histone mRNAs are not expected to be translated in axons, this finding may have resulted from enrichment of histone mRNAs lacking polyA tails. However, we previously found in patient fibroblasts that GANP may specifically influence the export of intronless gene mRNAs [61], and it is possible that histone genes, which are intronless, escape the regulation by mutant GANP in neurons. Indeed, we identified a subset of intronless genes that were differentially expressed in motor neurons and in the nuclear subcompartment (ADRA2A, PIGM, NORAD, ATXN7L3B).…”

Section: Ganp Regulates Gene Expression In Motor Neuronsmentioning

confidence: 97%

“…We have previously shown in patient fibroblasts that homozygous missense variants affecting the Sac3 domain of GANP do not alter MCM3AP mRNA or GANP protein levels, whereas compound heterozygous variants outside the Sac3 domain typically lead to lowered MCM3AP mRNA level and depletion of GANP at the nuclear membrane [61]. Here, we used immunostaining to detect GANP in the hiPSC lines.…”

Section: Mutation Type Affects Ganp Levels In Hipscmentioning

confidence: 98%

“…We also reprogrammed skin fibroblasts of patients FIN1 and FIN2, who carry V1272M and P148*fs48 compound heterozygous variants, which result in depletion of GANP [61,63], and of two healthy unrelated controls (Figure 1A,B).…”

Section: Mcm3ap Gene Edited and Patient-derived Hipsc Are Pluripotentmentioning

confidence: 99%

“…We and others recently identified GANP to underlie a childhood-onset neurological syndrome, caused by biallelic mutations in its encoding gene MCM3AP (MIM #618124, PNRIID) [23,24,49,61,63]. The disease affects peripheral nerves causing Charcot-Marie-Tooth neuropathy, and results in gait difficulties, often with loss of ambulation.…”

Section: Introductionmentioning

confidence: 99%

“…Many patients have intellectual disability. Variable other central nervous system involvement such as encephalopathy or epilepsy have been reported in some patients, as well as non-neurological symptoms such as ovarian dysfunction [61,63]. Studies in patient fibroblasts showed that pathological MCM3AP variants either result in a decrease in the amount of GANP at the nuclear envelope or affect critical amino acids in the Sac3 mRNA binding domain of GANP [61].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons

Woldegebriel

Kvist

White

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Loss-of-function of the mRNA export protein GANP (MCM3AP gene) cause early-onset sensorimotor neuropathy, characterised by axonal degeneration in long peripheral nerves. GANP functions as a scaffold at nuclear pore complexes, contributing to selective nuclear export of mRNAs. Here, we aimed to identify motor neuron specific transcripts that are regulated by GANP and may be limiting for local protein synthesis in motor neuron axons. We compared motor neurons with a gene edited mutation in the Sac3 mRNA binding domain of GANP to isogenic controls. We also examined patient-derived motor neurons. RNA sequencing of motor neurons as well as nuclear and axonal subcompartments showed that mutant GANP had a profound effect on motor neuron transcriptomes, with alterations in nearly 40 percent of all expressed genes and broad changes in splicing. Expression changes in multiple genes critical for neuronal functions, combined with compensatory upregulation of protein synthesis and early-stage metabolic stress genes, indicated that RNA metabolism was abnormal in GANP-deficient motor neurons. Surprisingly, limited evidence was found for large-scale nuclear retention of mRNA. This first study of neuropathy-linked GANP defects in human motor neurons shows that GANP has a wide gene regulatory role in a disease-relevant cell type that requires long-distance mRNA transport.

show abstract

Section: Ganp Regulates Gene Expression In Motor Neuronsmentioning

confidence: 97%

Section: Mutation Type Affects Ganp Levels In Hipscmentioning

confidence: 98%

Section: Mcm3ap Gene Edited and Patient-derived Hipsc Are Pluripotentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons

Woldegebriel

Kvist

White

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

The prevalence of inherited metabolic disorders in Estonian population over 30 years: A significant increase during study period

et al. 2022

Self Cite

View full text Add to dashboard Cite

Inherited metabolic disorders (IMD) are a group of hereditary diseases wherein the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease. Estonia's small population and nationwide digitalised healthcare system make it possible to perform an epidemiological study that covers the whole population. A study was performed in Tartu University Hospital, which is the only tertiary care unit in Estonia for diagnosing patients with IMD, to define the prevalence and live birth prevalence of IMDs and the effectiveness of new diagnostic methods on the diagnosis of IMD. During the retrospective study period from 1990 to 2017, 333 patients were diagnosed with IMD. Statistical analysis showed a significant increase in IMD diagnoses per year from 0.47 to 2.51 cases per 100 000 persons (p < 0.0001) during the study period. Live birth prevalence of IMD in Estonia was calculated to be 41.52 cases per 100 000 live births. The most frequently diagnosed IMD groups were disorders of amino acid metabolism, disorders of complex molecule degradation, mitochondrial disorders, and disorders of tetrapyrrole metabolism. Phenylketonuria was the most frequently diagnosed disorder of all IMD (21.6%). Our results correlated well with data from other developed countries and, along with high birth prevalence, add confidence in the effectiveness of our diagnostic yield. Implementation of new diagnostic methods during study period may largely account for the significant increase in the number of IMD diagnoses per year. We conclude that the implementation of new diagnostic methods continues to be important and contributes to better diagnosis of rare diseases.

show abstract

Genetic aspects of ataxias in a cohort of Turkish patients

Gogus,

Elmas,

Turk Boru

2024

Neurol Sci

View full text Add to dashboard Cite

Introduction Ataxia is one of the clinical findings of the movement disorder disease group. Although there are many underlying etiological reasons, genetic etiology has an increasing significance thanks to the recently developing technology. The aim of this study is to present the variants detected in WES analysis excluding non-genetic causes, in patients with ataxia. Methods Thirty-six patients who were referred to us with findings of ataxia and diagnosed through WES or other molecular genetic analysis methods were included in our study. At the same time, information such as the onset time of the complaints, consanguinity status between parents, and the presence of relatives with similar symptoms were evaluated. If available, the patient’s biochemical and radiological test results were presented. Results Thirty-six patients were diagnosed through WES or CES. The rate of detected autosomal recessive inheritance disease was 80.5%, while that of autosomal dominant inheritance disease was 19.5%. Abnormal cerebellum was detected on brain MRI images in 26 patients, while polyneuropathy was detected on EMG in eleven of them. While the majority of the patients were compatible with similar cases reported in the literature, five patients had different/additional features (variants in MCM3AP, AGTPBP1, GDAP2, and SH3TC2 genes). Conclusions The diagnosis of ataxia patients with unknown etiology is made possible thanks to these clues. Consideration of a genetic approach is recommended in patients with ataxia of unknown etiology.

show abstract

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Cited by 7 publications

References 43 publications

Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons

Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons

The prevalence of inherited metabolic disorders in Estonian population over 30 years: A significant increase during study period

Genetic aspects of ataxias in a cohort of Turkish patients

Contact Info

Product

Resources

About