Decreased mitochondrial DNA copy number in children with cerebral palsy quantified by droplet digital PCR

Lu, Bichao; Zeng, Fanyong; Xing, Wen; Lin, Liang; Huo, J M; Tan, Chianru; Zhu, Lingxiang; Liu, Zhizhong

doi:10.1016/j.cca.2020.01.018

Cited by 5 publications

(6 citation statements)

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“…In conjunction with these data, we observed lower levels of mtDNA/genomic DNA, indicating fewer mitochondria in CP skeletal muscle than in typically developing muscle. Our skeletal muscle data are supported by recent findings that children with CP also have reduced mitochondrial content in peripheral blood cells 28 . Blood‐based bioenergetic profiling correlates to physical function in older individuals 29 and has been suggested as a proxy for skeletal muscle oxidative capacity 30 .…”

Section: Discussionsupporting

confidence: 84%

Reduced mitochondrial DNA and OXPHOS protein content in skeletal muscle of children with cerebral palsy

Walden

Vechetti

Englund

et al. 2021

Develop Med Child Neuro

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Aim To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP). Method Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9–18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7–21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were analyzed with a focused query investigating metabolism‐ and mitochondria‐related gene networks. Results The mtDNA to genomic DNA ratio was lower in the children with CP compared to the typically developing group (−23%, p=0.002). Out of five investigated complexes in the mitochondrial respiratory chain, we observed lower protein levels of all complexes (I, III, IV, V, −20% to −37%; p<0.05) except complex II. Total peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) messenger RNA (p<0.004), isoforms PGC1α1 (p=0.05), and PGC1α4 (p<0.001) were reduced in CP. Transcriptional similarities were observed between CP, aging, and 90 days’ bed rest. Interpretation Mitochondrial biogenesis, mtDNA, and oxidative phosphorylation protein content are reduced in CP muscle compared with typically developing muscle. Transcriptional pathways shared between aging and long‐term unloading suggests metabolic dysregulation in CP, which may guide therapeutic strategies for combatting CP muscle pathology. Cerebral palsy (CP) muscle contains fewer energy‐generating organelles than typically developing muscle. Gene expression in CP muscle is similar to aging and long‐term bed rest.

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Section: Discussionsupporting

confidence: 84%

Reduced mitochondrial DNA and OXPHOS protein content in skeletal muscle of children with cerebral palsy

Walden

Vechetti

Englund

et al. 2021

Develop Med Child Neuro

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“…The ddPCR thermal profile was as follows: 95°C for 10 min, 40 cycles of 95°C for 30 s and 60°C for 1 min, and 1 cycle of 12°C for 5 min. Data analysis procedure was same as described in previous study ( 21 , 22 ).…”

Section: Methodsmentioning

confidence: 99%

“…Touch-down PCR was used with the following thermal cycling conditions: 94 C for 5 min. Data analysis procedure was same as described in previous study (21,22).…”

Section: Genetic Analysismentioning

confidence: 99%

Detection of Very Low-Level Somatic Mosaic COL4A5 Splicing Variant in Asymptomatic Female Using Droplet Digital PCR

et al. 2022

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BackgroundAlport syndrome is a hereditary glomerulopathy featured by haematuria, proteinuria, and progressive renal failure. X-linked Alport syndrome (XLAS) due to COL4A5 disease-causing variants is the most common form. In the case of XLAS resulting from 10–18% presumed de novo COL4A5 disease-causing variants, there are only a few studies for mosaicism in the probands or parents. Very low-level (<1.0%) somatic mosaicism for COL4A5 disease-causing variants has not been published.Materials and MethodsChinese XLAS families with suspected parental mosaicism were enrolled in the present study to evaluate the forms of mosaicism, to offer more appropriate genetic counseling. PCR and direct sequencing were used to detect COL4A5 disease-causing variants harbored by the affected probands in parental multi-tissue DNAs (peripheral blood, urine sediments, saliva, hair), and droplet digital PCR (ddPCR) was used to quantify the mutant COL4A5 allelic fractions in parental different samples such as peripheral blood, saliva, and urine sediments.ResultsA Chinese asymptomatic female with suspected somatic and germline mosaicism was enrolled in the present study. She gave birth to two boys with XLAS caused by a hemizygous disease-causing variant c. 2245-1G>A in COL4A5 (NM_033380) intron 28, whereas this disease-causing variant was not detected in genomic DNA extracted from peripheral blood leukocytes in the woman using Sanger sequencing. She had multiple normal urine test results, and continuous linear immunofluorescence staining of α2 (IV) and α5 (IV) chains of skin tissue. Sanger sequencing demonstrated that COL4A5 disease-causing variant c. 2245-1G>A was not detected in her genomic DNAs isolated from urine sediments, saliva, and hair roots. Using ddPCR, the wild-type and mutant-type (c.2245-1G>A) COL4A5 was identified in the female's genomic DNAs isolated from peripheral blood, saliva, and urine sediments. The mutant allelic fractions in these tissues were 0.26% (peripheral blood), 0.73% (saliva), and 1.39% (urine), respectively.ConclusionsGermline and very low-level somatic mosaicism for a COL4A5 splicing variant was detected in an asymptomatic female, which highlights that parental mosaicism should be excluded when a COL4A5 presumed de novo disease-causing variant is detected.

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“…18 Mitochondrial DNA is suggested to be a potential biomarker for many dysfunctions of mitochondria, and it is found to be related to many diseases including neurological diseases, traumatic brain injury, and autism. Lu et al 19 investigated the association of mitochondrial DNA copy number with CP and reported that a decline in mitochondrial DNA copy number implied mitochondrial dysfunction and CP. A study that was conducted reported that the mutation in mitochondrial DNA 8993 is associated with Leigh encephalopathy in children, where CP or other neurological impairment was found in other family members.…”

Section: Genetic or Epigenetic Implications In Cpmentioning

confidence: 99%

Dysregulation of multiple signaling pathways: A possible cause of cerebral palsy

Upadhyay

Ansari

Samad

et al. 2022

Exp Biol Med (Maywood)

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Cerebral palsy (CP) is a lifelong disability characterized by the impairment of brain functions that result in improper posture and abnormal motor patterns. Understanding this brain abnormality and the role of genetic, epigenetic, and non-genetic factors such as signaling pathway dysregulation and cytokine dysregulation in the pathogenesis of CP is a complex process. Hypoxic–ischemic injury and prematurity are two well-known contributors of CP. Like in the case of other neurodevelopmental disorders such as intellectual disability and autism, the genomic constituents in CP are highly complex. The neuroinflammation that is triggered by maternal cytokine response plays a critical role in the pathogenesis of fetal inflammation response, which is one of the contributing factors of CP, and it continues even after the birth of children suffering from CP. Canonical Wnt signaling pathway is important for the development of mammalian fetal brain and it regulates distinct processes including neurogenesis. The glycogen synthase kinase-3 (GSK-3) antagonistic activity in the Wnt signaling pathway plays a crucial role in neurogenesis and neural development. In this review, we investigated several genetic and non-genetic pathways that are involved in the pathogenesis of CP and their regulation, impairment, and implications for causing CP during embryonic growth and developmental period. Investigating the role of these pathways help to develop novel therapeutic interventions and biomarkers for early diagnosis and treatment. This review also helps us to comprehend the mechanical approach of various signaling pathways, as well as their consequences and relevance in the understanding of CP.

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Decreased mitochondrial DNA copy number in children with cerebral palsy quantified by droplet digital PCR

Cited by 5 publications

References 57 publications

Reduced mitochondrial DNA and OXPHOS protein content in skeletal muscle of children with cerebral palsy

Reduced mitochondrial DNA and OXPHOS protein content in skeletal muscle of children with cerebral palsy

Detection of Very Low-Level Somatic Mosaic COL4A5 Splicing Variant in Asymptomatic Female Using Droplet Digital PCR

Dysregulation of multiple signaling pathways: A possible cause of cerebral palsy

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