LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency

Abstract

SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome.

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

“…We also noted three loci with genome-wide significant associations containing genes ( KANSL1, PEX14 and LRPPRC ) implicated in rare, severe clinical syndromes characterized by phenotypes of progressive psychomotor impairment, muscle hypotonia and neuropathy2931. Within the UKB discovery cohort, the association of all three loci with grip strength persisted at genome-wide significance even after sensitivity analyses restricted to participants without any form of self-reported condition which might affect muscle mass or function.…”

“…2). rs10186876 ( P combined =9.75 × 10 −11 ) lies 15 kb upstream of LRPPRC (leucine-rich pentacotripeptide-containing), which has been implicated in the French-Canadian variant of Leigh Syndrome (MIM: 220111), a cytochrome C oxidase deficiency with features including developmental delay, hypotonia and weakness29. Mutations in PEX14 (Peroxisomal Biogenesis Factor 14) (intronic lead variant rs6687430) underlie certain forms of Zellweger Spectrum Peroxisomal Biogenesis Disorder (MIM: 614887), a syndrome characterized by absence of functional peroxisomes and systemic neurological impairment30.…”

Leigh syndrome: One disorder, more than 75 monogenic causes

“…patients, where no metabolic crises were observed in patients after the age of 7 years, 37 and suggested by the notably later median age at last report relative to the median age of death observed across patients with either PET100, NDUFV1, or MTFMT mutations in Figure 3. The particular vulnerability of the basal ganglia and brainstem structures to neurodegeneration in LS patients is unexplained.…”

“…37,40 Characteristic clinical features associated with French-Canadian LS (LSFC; MIM 220111) include mild facial dysmorphism, liver pathology, and a clinical course punctuated by episodes of acute metabolic decompensation that contribute significantly to mortality. 3,37 Fifty-five of 56 reported cases inherited homozygous LRPPRC p.A354V mutations, 37 reflecting a founder effect that has resulted in an incidence of LSFC of 1 in 2,000 live births (Table 3). 3 Broader effects of LRPPRC dysfunction on mitochondrial post-transcriptional and translation processes have recently been recognized, including deficiency of ATP synthase.…”

Accessorizing the human mitochondrial transcription machinery

“…Although reported to be in the cytoplasm and nucleus, its primary localization is in mitochondria [68], where it has multiple roles in RNA metabolism. Accordingly, mutations in the LRPPRC gene cause the inherited French Canadian variant of Leigh Syndrome (LSFC), a rare neurodegenerative disorder characterized by deficiency of mitochondrial OXPHOS complex IV (Cytochrome cOxidase, or COX) [64, 65, 67, 69]. …”