Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number

Abstract

In the originally published version of this article, Cristina Dallabona's first name was unfortunately misspelled.

MtDNA‐maintenance defects: syndromes and genes

“…This consideration requires a substantial expansion of the territory of gene hunting, well beyond that of the Busual suspects^. Second, mtDNA defects can be due to sporadic, heterozygous mutations, affecting singleton cases, as in the case of the recent identification of lethal de novo mutations in ANT1 (Thompson et al 2016). These cases can escape detection, particularly if the screening does not include parents and direct relatives of the proband.…”

“…However, de novo dominant mutations in SLC25A4 have recently been identified by whole exome sequencing in seven patients presenting with profound congenital hypotonia and muscle weakness, leading to death in the neonatal period. Profound mtDNA depletion and impairment of ATP transport capacity is the hallmark of this early onset form of ANT1-related disease(Thompson et al 2016). However, the reason why either recessive or dominant mutations in a monomeric protein(Bamber et al 2007)g i v e rise to such a wide spectrum of clinical and molecular phenotypes is still unknown.…”

Recent Advances in Mitochondrial Disease

“…Indeed, most of the candidate genes included on diagnostic virtual panels have their origins in research, which has been incredibly fruitful in elucidating genes involved in human pathology, including heterogeneous mitochondrial clinical phenotypes such as cardiomyopathy, with associated mutations identified in AARS2 (31), MRPL3 (22), MTO1 (24), and ACAD9 (33). The recent report of both biallelic and de novo dominant mutations affecting the novel mitochondrial disease gene ATAD3A (36) highlights the importance of thorough analysis of single heterozygous variants in presumed recessive etiologies and the concurrent analysis of parental samples; this is further highlighted by the recent expansion of the SLC25A4 mutation spectrum, which now includes de novo dominant mutations (92) in addition to the dominant and recessive mutations previously reported.…”

De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise

“…44 The phenotypes have been characterized in general by exercise intolerance, lactic acidosis, cardiomyopathy, myopathy, neuropathy, epilepsy, and microcephaly. 21 These disorders are all autosomal recessive, except for SLC25A4-related disorders, which are inherited either autosomal-recessively (autosomal-recessive, cardiomyopathic-type mitochondrial DNA depletion syndrome 12B [MIM: 615418]) 45 or autosomal-dominantly (autosomal-dominant, cardiomyopathic-type mitochondrial DNA depletion syndrome 12A [MIM: 617184] 46 and autosomal-dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 2 [MIM: 609283]). 47 Mutations in SLC25A4, which encodes a mitochondrial ADP/ATP carrier, cause mtDNA instability through a currently unknown mechanism.…”

“…47 Mutations in SLC25A4, which encodes a mitochondrial ADP/ATP carrier, cause mtDNA instability through a currently unknown mechanism. 46,47 Additionally, increased mtDNA point mutations and deletions, 48 mtDNA replication arrest, 49 and abnormalities of stem cell renewal 50 have been reported in POLG mutator mice with a premature-aging phenotype. Given that the disease phenotype of Fontaine syndrome could be a consequence of mtDNA instability, we performed a search for de novo point mutations and structural variants in mtDNA of two probands and found no evidence of an increase in the rate of de novo mtDNA mutation events (Table S2).…”