4H Syndrome With Late-Onset Growth Hormone Deficiency Caused by POLR3A Mutations

Potic, Ana; Brais, Bernard; Choquet, Karine; Schiffmann, Raphael; Bernard, Geneviève

doi:10.1001/archneurol.2011.1963

Cited by 55 publications

(45 citation statements)

References 18 publications

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“…This study, which used molecular modeling based on comparisons of yeast pols II and III strongly supports the idea that the RPC2-RPC11 interface is similar to the RPB2-RPB9 interface and functionally conserved from yeast to vertebrates [89]. In addition, sjm was the first to reveal that mutations in a pol III subunit, a housekeeping enzyme, can have devastating tissue-specific phenotypic effects [98], including in humans [99–102]. …”

Section: Pol III Subunits Involved In Terminationsupporting

confidence: 61%

Transcription termination by the eukaryotic RNA polymerase III

Arimbasseri

Rijal

Maraia

2013

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

112

111

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RNA polymerase (pol) III transcribes a multitude of tRNA and 5S rRNA genes as well as other small RNA genes distributed through the genome. By being sequence-specific, precise and efficient, transcription termination by pol III not only defines the 3′ end of the nascent RNA which directs subsequent association with the stabilizing La protein, it also prevents transcription into downstream DNA and promotes efficient recycling. Each of the RNA polymerases appears to have evolved unique mechanisms to initiate the process of termination in response to different types of termination signals. However, in eukaryotes much less is known about the final stage of termination, destabilization of the elongation complex with release of the RNA and DNA from the polymerase active center. By comparison to pols I & II, pol III exhibits the most direct coupling of the initial and final stages of termination, both of which occur at a short oligo(dT) tract on the non-template strand (dA on the template) of the DNA. While pol III termination is autonomous involving the core subunits C2 and probably C1, it also involves subunits C11, C37 and C53, which act on the pol III catalytic center and exhibit homology to the pol II elongation factor TFIIS, and TFIIFα/β respectively. Here we compile knowledge of pol III termination and associate mutations that affect this process with structural elements of the polymerase that illustrate the importance of C53/37 both at its docking site on the pol III lobe and in the active center. The models suggest that some of these features may apply to the other eukaryotic pols.

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Section: Pol III Subunits Involved In Terminationsupporting

confidence: 61%

Transcription termination by the eukaryotic RNA polymerase III

Arimbasseri

Rijal

Maraia

2013

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

112

111

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“…Yet, POLR3A sequencing should be prioritised for genetic testing since 73% (27/37) of all patients in our cohort carry mutations in POLR3A and 27% (10/37) of patients have mutations in POLR3B 4 5 7. On the other hand, when mutations in POLR3A are ruled out, POLR3B should be sequenced.…”

Section: Discussionmentioning

confidence: 99%

Mutations inPOLR3AandPOLR3Bare a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism

et al. 2013

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“…Cerebellar dysfunction is the most frequent neurological abnormality [7, 10–13, 21], and the majority of patients also have cognitive dysfunction [1, 6, 7, 9, 12, 18, 22]. Progressive neurological deterioration is a characteristic feature of patients with 4H leukodystrophy and other Pol III-related leukodystrophies, with many patients becoming wheelchair-bound and exhibiting significant cognitive impairment by the time they reach young adulthood [1, 7, 10, 13, 18, 21, 23].…”

Section: Discussionmentioning

confidence: 99%

“…The majority of females with 4H leukodystrophy lack spontaneous pubertal development, suggesting that hypogonadotropic hypogonadism is usually established prior to adolescence in this disorder [12, 13]. Although hypogonadism has not been recognized until early adulthood in some male patients, normal initial pubertal development followed by progressive hypogonadism has not been described [9, 10]. Some patients also have growth hormone deficiency, which was shown to be progressive in one individual [9, 12].…”

Section: Discussionmentioning

confidence: 99%

“…Although hypogonadism has not been recognized until early adulthood in some male patients, normal initial pubertal development followed by progressive hypogonadism has not been described [9, 10]. Some patients also have growth hormone deficiency, which was shown to be progressive in one individual [9, 12]. The other pituitary hormones do not appear to be affected.…”

Section: Discussionmentioning

confidence: 99%

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Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature

Billington

Bernard

Gibson

et al. 2015

Case Reports in Endocrinology

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Introduction. 4H leukodystrophy is an autosomal recessive RNA polymerase III-related leukodystrophy, characterized by hypomyelination, with or without hypodontia (or other dental abnormalities) and hypogonadotropic hypogonadism. Case Presentation. We describe a 28-year-old female who presented with primary amenorrhea at the age of 19. She had a history of very mild neurological and dental abnormalities. She was found to have hypogonadotropic hypogonadism, and magnetic resonance imaging of the brain showed hypomyelination. The diagnosis of 4H leukodystrophy was made. She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III. She wished to become pregnant and failed to respond to pulsatile GnRH but achieved normal follicular growth and ovulation with subcutaneous gonadotropin therapy. Discussion. Patients with 4H leukodystrophy may initially present with hypogonadotropic hypogonadism, particularly if neurological and dental manifestations are subtle. Making the diagnosis has important implications for prognosis and management. Progressive neurologic deterioration is expected, and progressive endocrine dysfunction may occur. Patients with 4H leukodystrophy should be counseled about disease progression and about this disease's autosomal recessive inheritance pattern. In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective.

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4H Syndrome With Late-Onset Growth Hormone Deficiency Caused by POLR3A Mutations

Cited by 55 publications

References 18 publications

Transcription termination by the eukaryotic RNA polymerase III

Transcription termination by the eukaryotic RNA polymerase III

Mutations inPOLR3AandPOLR3Bare a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism

Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature

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