Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Abstract

Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p. G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.gene identification | neurodegenerative disease | mitochondrial dysfunction | DNA sequencing | mutation

Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria

“…A more direct role of the p.Gly399Ser HTRA2 mutant allele in essential tremor and Parkinson's disease was initially suggested but later disputed 24 25. Thus, this is the first report of recessive deleterious mutations in HTRA2 in human.…”

Essential tremor

“…More recently, in a six-generation consanguineous Turkish kindred with both ET and Parkinson disease, the mitochondrial serine protease HTRA2 p.G399S variant was shown to segregate with both phenotypes (Parkinson disease and ET). All affected individuals in the family were either heterozygous or homozygous for the HTRA2 variant and homozygosity was associated with earlier age at onset of tremor ( p < 0.0001), more severe postural tremor ( p < 0.0001), and more severe kinetic tremor ( p = 0.0019) (Unal Gulsuner et al, 2014). Follow-up studies in ET family studies and case-control studies will be needed to determine whether HTRA2 represents a major ET susceptibility gene (Clark and Louis, 2015).…”

Genetics of essential tremor

“…More recently, exome sequencing of a large ET family of French-Canadian origin has identified a pathogenic variant of FUS [MIM 137070] [14]. This is followed by identifications of HTRA2 [MIM 606441] from a six-generation consanguineous Turkish kindred [15] and pathogenic variants in the TENM4 [MIM 610084] gene from a Spanish population [16].…”

“…Genetic links between ET and PD involves the LINGO1 [26], HTRA2 [15], Lrrk2 [27] and DNAJC13 [28] genes. In some families, although an allele is known to be responsible for hereditary ET, homozygotes can later develop PD [15]. Phenotypic and genotypic heterogeneity are also reflected by differential response by patients towards symptomatic drug treatments [29].…”