Severe telomere shortening in Fanconi anemia complementation group L

Shah, Anjali; George, Merin; Dhangar, Somprakash; Rajendran, Aruna; Mohan, Sheila; Vundinti, Babu Rao

doi:10.1007/s11033-020-06101-2

Cited by 7 publications

(2 citation statements)

References 25 publications

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“…Although the telomere shorting in our HFF-shCOX4I1 in vitro cell system was less prominent (Fig. S1A) than in blood cells from common FA complementation groups, the similarity is evident [23]. Indeed, recently, FA has been re-de ned as an accelerated aging (AA) diseases (including premature aging syndromes and aging-associated diseases) [24].…”

Section: Discussionmentioning

confidence: 85%

Mitochondrial COX4-1 deficiency leads to impaired nuclear DNA damage response resulting in proliferation deficits and premature senescence

Douiev

Miller

Benyamini

et al. 2021

Preprint

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Cytochrome- c- oxidase (COX), a multimeric protein complex, is the final electron acceptor in the mitochondrial electron transfer chain. Primary COX deficiency, caused by mutations in either mitochondrial DNA or nuclear-encoded genes, is a heterogenous group of mitochondrial diseases with a wide range of presentations ranging from fatal infantile to subtler. We previously reported a patient with primary COX deficiency due to a pathogenic variant in COX4I1 (encoding the common isoform of COX subunit 4), who presented with bone-marrow failure, genomic instability and short stature, mimicking Fanconi anemia (FA). In the present study, we demonstrated reduced proliferation and premature senescence in this patient’s fibroblasts and in COX4-1 knockdown cells. Accumulative DNA damage coincided primarily with proliferative cells, indicating replicative stress. Expression analysis implicated DNA damage response which was verified by demonstrating impaired recovery from genotoxic insult and decreased DNA repair. Interestingly, our in-vitro findings recapitulate the patient’s presentation and present status. Thus, we suggest that the premature senescence, resulting from accumulative DNA damage in COX4-1 deficiency is a protective mechanism to avoid malignant transformation in a similar manner to what was reported for FA and other “accelerated aging diseases”.

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Section: Discussionmentioning

confidence: 85%

Mitochondrial COX4-1 deficiency leads to impaired nuclear DNA damage response resulting in proliferation deficits and premature senescence

Douiev

Miller

Benyamini

et al. 2021

Preprint

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“…Thus, the telomere has been referred to as a "mitotic clock" [12] and telomere length has been construed as a measure of "biological age" [13]. Consistent with these considerations, peripherally measured TL has been shown to be associated with a wide range of disease and health morbidities in adults [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] and children [29][30][31][32][33][34][35][36][37][38] and has become a popular biomarker for stress and accelerated biological aging [10,35,[39][40][41][42][43][44][45]. Thus, TL at birth and the course of TL shortening in blood or saliva may provide insight into associated between premature birth and future health trajectory.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of salivary telomere length shortening in preterm infants

et al. 2023

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Objective To examine the association between gestational age, telomere length (TL) and rate of shortening in newborns. Study design Genomic DNA was isolated from buccal samples of 39 term infants at birth and one year and 32 preterm infants at birth, term-adjusted age (40 weeks post-conception) and age one-year corrected for gestational duration. Telomere length was measured by quantitative real-time PCR. Demographic and clinical data were collected during clinic or research visits and from hospital records. Socioeconomic status was estimated using the deprivation category (DEPCAT) scores derived from the Carstairs score of the subject’s postal code. Results At birth, preterm infants had longer telomeres than infants born at term. However, there was no difference in telomere length between preterm infants and term infants at one year of age, implying that the rate of telomere shortening was greater in pre-term than term infants. Interestingly, TL at age 40 weeks post-conception in preterm infants was significantly longer than term infant TL at birth, suggesting that time since conception is not the only factor that affects rate of shortening. Several factors, including sex, fetal growth restriction, maternal age, maternal booking body mass index (BMI), mother education level and DEPCAT score, also differed between the preterm and term groups. Conclusions Preterm infants have longer telomeres than term infants at birth. In the studied cohort, the rate of telomere shortening was greater in the premature group compared with the term infants. This finding agrees with previous studies using cord blood, suggesting that the longer TL in premature infants detected at birth do not persist and demonstrating that use of saliva DNA is acceptable for studies of telomere dynamics in infants. However, that the TL at age 40 weeks post-conception in preterm is longer than term infants at birth suggests that biological factors other than time since conception also affect rate of shortening.

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