Loss-of-Function Mutations in<i>PNPLA6</i>Encoding Neuropathy Target Esterase Underlie Pubertal Failure and Neurological Deficits in Gordon Holmes Syndrome

Topaloğlu, Ali Kemal; Lomniczi, Alejandro; Kretzschmar, Doris; Dissen, Gregory A.; Kotan, Leman Damla; McArdle, Craig A.; Koç, Altuğ; Hamel, B.C.J.; Güçlü, Metin; Papatya, Esra D.; Eren, Erdal; Mengen, Eda; Gürbüz, Fatih; Cook, Mandy; Castellano, Juan Manuel Parreño; Kekil, M. Burcu; Mungan, Neslihan; Yüksel, Bilgin; Ojeda, Sergio R.

doi:10.1210/jc.2014-1836

Cited by 91 publications

(73 citation statements)

References 31 publications

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“…51 Interestingly, data from the past few years suggest that the actual number of kisspeptin and/or NKB neurons might change during development. 52,53 Mutations in proteins that regulate ubiquitination such as OTU domain-containing protein 4 (encoded by OTUD4) and E3 ubiquitin-protein ligase RNF216 (also known as ring finger protein 216; encoded by RNF216), 54 as well as in proteins involved in lipid metabolism such as neuropathy target esterase (also known as patatin-like phospholipase domain-containing protein 6; encoded by PNPLA6) 55,56 have been identified in patients with Gordon Holmes syndrome (with associated CHH and ataxia). Thus, mutations in these three genes give rise to a broad and progressive neurodegenerative syndrome that includes CHH.…”

Section: Virilization (Male)mentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Section: Virilization (Male)mentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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“…Mutations in POLR3A/B result in the 4H syndrome (hypomyelination, hypodontia, and hypogonadotropic hypogonadism) [36], whilst those in RNF216, OTUD4, and PNPLA6 produce the phenotypic combination of HH and ataxia (also known as Gordon Holmes syndrome) [37,38]. DMXL2 mutations are associated with congenital HH, other endocrine deficiencies, and polyneuropathies [39].…”

Section: Genetics Of Gnrh Deficiency or Signallingmentioning

confidence: 99%

The Genetic Basis of Delayed Puberty

Howard

2017

Neuroendocrinology

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The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Some insights into the genetic mutations that lead to familial DP have come from sequencing genes known to cause gonadotropin-releasing hormone (GnRH) deficiency, most recently via next-generation sequencing, and others from large-scale genome-wide association studies in the general population. Investigation of the genetic control of DP is complicated by the fact that this trait is not rare and that the phenotype is likely to represent a final common pathway, with a variety of different pathogenic mechanisms affecting the release of the puberty “brake.” These include abnormalities of GnRH neuronal development and function, GnRH receptor and luteinizing hormone/follicle-stimulating hormone abnormalities, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Thus, genetic control of pubertal timing can range from early fetal life via development of the GnRH network to those factors directly influencing the puberty brake during mid-childhood.

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“…Among the syndromes associated with mutations in PNPLA6 are: Gordon Holmes ( 22,23 ) and Boucher-Neuhauser ( 23 ), characterized by early-onset ataxia and hypogonadism; Oliver-McFarlane ( 24 ), characterized by trichomegaly, congenital hypopituitarism, retinal degeneration, and choroidal atrophy; Laurence-Moon ( 24 ), characterized by progressive spinocerebellar ataxia and spastic paraplegia; and photoreceptor degeneration and childhood blindness ( 25 ). An NTE-related iPLA 2 (PNPLA7) awaits further characterization ( 9, 10 ).…”

mentioning

confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

158

170

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The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

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Loss-of-Function Mutations inPNPLA6Encoding Neuropathy Target Esterase Underlie Pubertal Failure and Neurological Deficits in Gordon Holmes Syndrome

Abstract: These results suggest that NTE-dependent alteration of phospholipid homeostasis in GHS causes both neurodegeneration and impaired LH release from pituitary gonadotropes, leading to nHH.

Cited by 91 publications

References 31 publications

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

The Genetic Basis of Delayed Puberty

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

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