Biallelic LINE insertion mutation in
            <i>HACD1</i>
            causing congenital myopathy

Amrani, Fatema Al; Gorodetsky, Carolina; Hazrati, Lili‐Naz; Amburgey, Kimberly; Gonorazky, Hernan; Dowling, James J.

doi:10.1212/nxg.0000000000000423

Cited by 5 publications

(7 citation statements)

References 7 publications

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“…Notably, expression of the HACD1 active isoform is restricted to the heart and skeletal muscle, in which it promotes efficient myoblast fusion during muscle development (20). While HACD1 deficiency leads to congenital myopathies in humans, dogs, and mice sharing an early and stable reduction in muscle mass and strength (20)(21)(22)(23), the metabolic consequences of HACD1 deficiency remained to be deciphered.…”

Section: Introductionmentioning

confidence: 99%

Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle

et al. 2021

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Unbalanced energy partitioning participates in the rise of obesity, a major public health concern in many countries. Increasing basal energy expenditure has been proposed as a strategy to fight obesity yet raises efficiency and safety concerns. Here, we show that mice deficient for a muscle-specific enzyme of very-long-chain fatty acid synthesis display increased basal energy expenditure and protection against high-fat diet–induced obesity. Mechanistically, muscle-specific modulation of the very-long-chain fatty acid pathway was associated with a reduced content of the inner mitochondrial membrane phospholipid cardiolipin and a blunted coupling efficiency between the respiratory chain and adenosine 5′-triphosphate (ATP) synthase, which was restored by cardiolipin enrichment. Our study reveals that selective increase of lipid oxidative capacities in skeletal muscle, through the cardiolipin-dependent lowering of mitochondrial ATP production, provides an effective option against obesity at the whole-body level.

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Section: Introductionmentioning

confidence: 99%

Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle

et al. 2021

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“…Schematic representation of the HACD1 mRNA transcript (ENST00000361271.8) and the predicted impact at the cDNA level of the newly identified variants. The positions of variants detected in our patients (black) and previously reported changes 5,6 (gray) are indicated above the transcript. The 3′ and 5′ untranslated regions are shown as gray boxes and the seven HACD1 exons as numbered white boxes.…”

Section: Resultsmentioning

confidence: 85%

“…To date, two different truncating HACD1 variants have been reported in human congenital myopathy patients (Figure 1(A), Table 1). A homozygous nonsense variant in exon 6 (c. 744C>T, p.Tyr248*) was identified in eight affected members of a Bedouin family, 5 while a homozygous long interspersed nuclear element (LINE) insertion (c.739_740delins1250) has been reported in the same HACD1 exon in a female patient of Sri Lankan ancestry 6 . Biopsies in patients with these variants indicated a CFTD‐type of myopathy, 5,6 and HACD1 mRNA levels were reduced by 69% in one of the patients harboring the nonsense variant 5 .…”

Section: Discussionmentioning

confidence: 98%

“…A homozygous nonsense variant in exon 6 (c. 744C>T, p.Tyr248*) was identified in eight affected members of a Bedouin family, 5 while a homozygous long interspersed nuclear element (LINE) insertion (c.739_740delins1250) has been reported in the same HACD1 exon in a female patient of Sri Lankan ancestry 6 . Biopsies in patients with these variants indicated a CFTD‐type of myopathy, 5,6 and HACD1 mRNA levels were reduced by 69% in one of the patients harboring the nonsense variant 5 . Importantly, pectus excavatum was observed in two patients from the Bedouin family and in our Patient Three – indicating that pectus deformity might be a relatively common finding associated with HACD1 ‐related myopathy (Table 1).…”

Section: Discussionmentioning

confidence: 98%

“…CoA dehydratase) gene has been identified as causes of an autosomal recessive CFTD type of congenital myopathy 5,6 . In addition, an exonic short interspersed nuclear element (SINE) insertion into canine HACD1 results in the manifestation of autosomal recessive core myopathy in Labrador retrievers.…”

Section: Introductionmentioning

confidence: 99%

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Biallelic loss‐of‐function HACD1 variants are a bona fide cause of congenital myopathy

et al. 2021

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Congenital myopathies include a wide range of genetically determined disorders characterized by muscle weakness that usually manifest shortly after birth. To date, two different homozygous loss‐of‐function variants in the HACD1 gene have been reported to cause congenital myopathy. We identified three patients manifesting with neonatal‐onset generalized muscle weakness and motor delay that carried three novel homozygous likely pathogenic HACD1 variants. The two of these changes (c.373_375+2delGAGGT and c.785‐1G>T) were predicted to introduce splice site alterations, while one is a nonsense change (c.458G>A). The clinical presentation of our and the previously reported patients was comparable, including the temporally progressive improvement that seems to be characteristic of HACD1‐related myopathy. Our findings conclusively confirm the implication of HACD1 in the pathogenesis of congenital myopathies, corroborate the main phenotypic features, and further define the genotypic spectrum of this genetic form of myopathy. Importantly, the genetic diagnosis of HACD1‐related myopathy bears impactful prognostic value.

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