Gonadal dysgenesis as an autosomal recessive condition

Christakos, Arthur C.; Simpson, Joe Leigh; Younger, J. Benjamin; Christian, Charles L.

doi:10.1016/0002-9378(69)90697-8

Cited by 37 publications

(20 citation statements)

References 12 publications

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“…Perrault syndrome was first defined in 1951 as ovarian dysgenesis and sensorineural hearing loss in females [12]. Brothers of Perrault syndrome females have been reported with hearing loss but are reportedly fertile [13]. Perrault syndrome is genetically heterogeneous and recessive mutations in three additional genes have been implicated to date, including HARS2 , LARS2 , and CLPP , which respectively encode the mitochondrial histidyl- and leucyl-tRNA synthetases and a mitochondrial ATP-dependent protease [14-17].…”

Section: Discussionmentioning

confidence: 99%

Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency

et al. 2014

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BackgroundD-bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe, infantile-onset disorder of peroxisomal fatty acid oxidation. Few affected patients survive past two years of age. Compound heterozygous mutations in HSD17B4 have also been reported in two sisters diagnosed with Perrault syndrome (MIM # 233400), who presented in adolescence with ovarian dysgenesis, hearing loss, and ataxia.Case presentationAn adult male presented with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia. The clinical presentation, in combination with biochemical findings in serum, urine, and muscle biopsy, suggested a mitochondrial disorder. Commercial genetic testing of 18 ataxia and mitochondrial disease genes was negative. Targeted exome sequencing followed by analysis of single nucleotide variants and small insertions/deletions failed to reveal a genetic basis of disease. Application of a computational algorithm to infer copy number variants (CNVs) from exome data revealed a heterozygous 12 kb deletion of exons 10–13 of HSD17B4 that was compounded with a rare missense variant (p.A196V) at a highly conserved residue. Retrospective review of patient records revealed mildly elevated ratios of pristanic:phytanic acid and arachidonic:docosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation.ConclusionOur case expands the phenotypic spectrum of HSD17B4-deficiency, representing the first male case reported with infertility. Furthermore, it points to crosstalk between mitochondria and peroxisomes in HSD17B4-deficiency and Perrault syndrome.

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Section: Discussionmentioning

confidence: 99%

Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency

et al. 2014

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“…Short stature and variable mental retardation were also reported [Christakos et al, 1969;Perez-Ballester et al, 1970;Pallister and Opitz, 1979;Bösze et al, 1983;McCarthy and Opitz, 1985;Nishi et al, 1998]. Recently, Linssen et al [1994] and Gottschalk et al [1996] focused on the neurological signs in patients with Perrault syndrome (PS).…”

Section: Introductionmentioning

confidence: 99%

Perrault syndrome: Evidence for progressive nervous system involvement

Fiumara

Sorge

Toscano

et al. 2004

American J of Med Genetics Pt A

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Perrault syndrome (PS) comprises gonadal dysgenesis and sensorineural deafness in females, and deafness in affected males. More recent studies have asked whether the neurological signs in some of the patients are a coincidental finding or part of the syndrome. We report on two pairs of sisters with gonadal dysgenesis and deafness, cerebral, and ocular involvement who developed a progressive, severe sensory, and motor neuropathy. This observation constitutes further evidence of peripheral nervous system involvement in PS. Based on the clinical observations of known patients, two forms of PS may be distinguished: one apparently non-progressive form and another (exemplified by our two sets of sisters) with apparently progressive axonal-cerebellar degeneration.

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“…P errault syndrome is a rare recessive disorder characterized by ovarian dysgenesis in females and sensorineural hearing loss in females and males (1). Affected females are karyotypically 46XX and infertile; affected males are 46XY and fertile (2). The syndrome is clinically heterogeneous: Some families have only sensorineural hearing loss and female ovarian dysgenesis, whereas others have neurological manifestations, which can include ataxia, limited extraocular movements, nystagmus, ophthalmoplegia, lower limb weakness, mental retardation, sensory polyneuropathy, hypotonia, or poor reflexes (3)(4)(5).…”

mentioning

confidence: 99%

Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome

Pierce

Chisholm

Lynch

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

234

198

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Perrault syndrome is a genetically heterogeneous recessive disorder characterized by ovarian dysgenesis and sensorineural hearing loss. In a nonconsanguineous family with five affected siblings, linkage analysis and genomic sequencing revealed the genetic basis of Perrault syndrome to be compound heterozygosity for mutations in the mitochondrial histidyl tRNA synthetase HARS2 at two highly conserved amino acids, L200V and V368L. The nucleotide substitution creating HARS2 p.L200V also created an alternate splice leading to deletion of 12 codons from the HARS2 message. Affected family members thus carried three mutant HARS2 transcripts. Aminoacylation activity of HARS2 p.V368L and HARS2 p.L200V was reduced and the deletion mutant was not stably expressed in mammalian mitochondria. In yeast, lethality of deletion of the single essential histydyl tRNA synthetase HTS1 was fully rescued by wild-type HTS1 and by HTS1 p.L198V (orthologous to HARS2 p.L200V), partially rescued by HTS1 p.V381L (orthologous to HARS2 p.V368L), and not rescued by the deletion mutant. In Caenorhabditis elegans, reduced expression by RNAi of the single essential histydyl tRNA synthetase hars-1 severely compromised fertility. Together, these data suggest that Perrault syndrome in this family was caused by reduction of HARS2 activity. These results implicate aberrations of mitochondrial translation in mammalian gonadal dysgenesis. More generally, the relationship between HARS2 and Perrault syndrome illustrates how causality may be demonstrated for extremely rare inherited mutations in essential, highly conserved genes.

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Gonadal dysgenesis as an autosomal recessive condition

Cited by 37 publications

References 12 publications

Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency

Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency

Perrault syndrome: Evidence for progressive nervous system involvement

Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome

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