Phenotypic continuum of <scp><i>NFU1</i></scp>‐related disorders

Kaiyrzhanov, Rauan; Zaki, Maha S.; Lau, Tracy; Sen, Sambuddha; Azizimalamiri, Reza; Zamani, Mina; Sayın, Gözde Yeşil; Hilander, Taru; Efthymiou, Stephanie; Chelban, Viorica; Brown, Ruth; Thompson, Kyle; Scarano, Maria I.; Ganesh, Jaya; Koneev, Kairgali; Gülaçar, Ismail Musab; Person, Richard; Sadykova, Dinara; Maidyrov, Yerdan; Seifi, Tahereh; Zadagali, Aizhan; Bernard, Geneviève; Allis, Katrina; Elloumi, Houda Zghal; Lindy, Amanda; Taghiabadi, Ehsan; Verma, Sumit; Logan, Rachel; Kirmse, Brian; Bai, Renkui; Khalaf, Shaimaa M; Abdel‐Hamid, Mohamed S.; Sedaghat, Alireza; Shariati, Gholamreza; Issa, Mahmoud Y.; Zeighami, Jawaher; Elbendary, Hasnaa M; Brown, Garry K.; Taylor, Robert W.; Galehdari, Hamid; Gleeson, Joseph J; Carroll, Christopher J.; Cowan, J. A.; Moreno-De-Luca, Andrés; Houlden, Henry; Maroofian, Reza

doi:10.1002/acn3.51679

Cited by 1 publication

(1 citation statement)

References 23 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MMDS1–5 have different clinical features. MMDS1 specifically causes pulmonary hypertension 30 , 31 ; MMDS2 causes dilated cardiomyopathy 32 ; MMDS3 has a milder clinical phenotype, which may be related to the residual efficiency of mutant IBA57; MMDS4 and MMDS5 have similar symptoms such as seizures in infancy, spasticity, nystagmus, sensorineural hearing loss. The different symptoms of MMDS1–5 may be due to the different functions of the corresponding proteins during [4Fe‐4S] synthesis.…”

Section: Discussionmentioning

confidence: 99%

A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

Sheng

et al. 2023

Anim Models and Exp Med

View full text Add to dashboard Cite

Background Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death. Methods We generated neuron‐specific Isca1 knockout rat (Isca1flox/flox ‐NeuN‐Cre) using CRISPR‐Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons. Results This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis. Conclusions This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.

show abstract

Section: Discussionmentioning

confidence: 99%