The perrault syndrome: Autosomal recessive ovarian dysgenesis with facultative, non‐sex‐limited sensorineural deafness

Pd, Pallister; Jm, Opitz

doi:10.1002/ajmg.1320040306

Cited by 68 publications

(45 citation statements)

References 5 publications

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“…59 In some forms the defect is restricted to the gonads, whereas in others affected females show neurosensory hearing loss (Perrault syndrome). 60,61 In a subset of patients with ovarian dysgenesis, mutations in the FSH receptor gene were detected. 62 Gonadal dysgenesis has also been associated with major X chromosome abnormalities.…”

Section: Gonadal Dysgenesismentioning

confidence: 99%

Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals

Kousta¹,

Papathanasiou²,

Skordis³

2010

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There have been considerable advances concerning understanding of the early and later stages of ovarian development; a number of genes have been implicated and their mutations have been associated with developmental abnormalities. The most important genes controlling the initial phase of gonadal development, identical in females and males, are Wilms' tumor suppressor 1 (WT1) and steroidogenic factor 1 (SF1). Four genes are likely to be involved in the subsequent stages of ovarian development (WNT4, DAX1, FOXL2 and RSPO1), but none is yet proven to be the ovarian determining factor. changes in nomenclature and classification were recently proposed in order to incorporate genetic advances and substitute gender-based diagnostic labels in terminology. The term "disorders of sex development" (DsD) is proposed to substitute the previous term "intersex disorders". Three main categories have been used to describe DsD in the 46,XX individual: 1) disorders of gonadal (ovarian) development: ovotesticular DsD, previously named true hermaphroditism, testicular DsD, previously named XX males, and gonadal dysgenesis; 2) disorders related to androgen excess (congenital adrenal hyperplasia, aromatase deficiency and P450 oxidoreductase deficiency); and 3) other rare disorders. In this mini-review, recent advances concerning development of the genital system in 46,XX individuals and related abnormalities are discussed. basic embryology of the ovary and molecular pathways determining ovarian development are reviewed, focusing on mutations disrupting normal ovarian development. Disorders of sex development according to the revised nomenclature and classification in 46,XX individuals are summarized, including genetic progress in the field.

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Section: Gonadal Dysgenesismentioning

confidence: 99%

Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals

Kousta¹,

Papathanasiou²,

Skordis³

2010

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“…The goal of the present study was to identify and characterize the genetic basis of Perrault syndrome in one of the first reported kindreds (11) (Fig. 1A).…”

mentioning

confidence: 99%

“…All persons in the family had normal intelligence. Thorough clinical evaluation of the family was provided by Pallister and Opitz (11).…”

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.

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236

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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“…These include Perrault syndrome, Werner syndrome, Bloom syndrome and ataxia-telangiectasia. 11,12 However, the absence of mental retardation, neurological findings, neurosensory hearing loss and other anomalies in this patient eliminates these and other possible diagnoses.…”

Section: Figurementioning

confidence: 70%

Achondroplasia Associated with Gonadal Dysgenesis

et al. 2008

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The perrault syndrome: Autosomal recessive ovarian dysgenesis with facultative, non‐sex‐limited sensorineural deafness

Cited by 68 publications

References 5 publications

Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals

Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals

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

Achondroplasia Associated with Gonadal Dysgenesis

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