scholarly journals Defects in the GnRH Neuronal Migration factor, CCDC141, Lead to Self-Limited Delayed Puberty

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A665-A666
Author(s):  
Tansit Saengkaew ◽  
Alessandra Mancini ◽  
Gerard Ruiz-Babot ◽  
Claudia P Cabrera ◽  
Michael R Barnes ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neuronal Migration ◽  
Hypogonadotropic Hypogonadism ◽  
Hek293 Cells ◽  
Delayed Puberty ◽  
Compound Heterozygous ◽  
Critical Element ◽  
Incomplete Penetrance ◽  
Inheritance Pattern ◽  
Foetal Development

Abstract GnRH neuronal biology has been identified as a critical element in the pathogenesis of self-limited DP, previously implicated exclusively in the pathophysiology of idiopathic hypogonadotropic hypogonadism (IHH). We hypothesise that this condition may be inherited via genetic variants discoverable through whole-exome sequencing (WES), by focusing on genes involved in GnRH neuron development and function, and genes reported in IHH. We analysed WES data from large Finnish cohort with familial self-limited DP, focusing on genes recently reported in IHH. WES data of 100 DP families have been analysed with a total of 193 individuals: 100 probands, 158 affected and 35 unaffected family members. Potentially pathogenic rare variants segregating within cohort families were identified using a virtual panel of recently reported IHH genes (n=13). This analysis identified 6 rare potentially pathogenic variants in CCDC141 in 25 individuals of 8 families which account for almost 10% of self-limited DP cases in this cohort, without variants identified in cohort control cases. Previous studies reported that homozygous or compound heterozygous mutations of CCDC141 cause Kallmann syndrome and IHH, due to impaired GnRH neuronal migration. In this study, all 6 CCDC141 variants were heterozygous missense variants predicted to be deleterious by in silico prediction tools. Most probands were male (n=7) with typical features of self-limited DP, with absence of secondary sexual characteristics, delayed bone age, and low gonadotropins and sex steroids at first presentation and spontaneous entry into puberty later than age of 14 years without treatment. The majority of pedigrees displayed good segregation of variants with the DP trait, following an autosomal dominant inheritance pattern. However, in two families, there was a complex inheritance pattern with compound heterozygosity (p.Ser55Cys and p.Asp767Asn) and possible incomplete penetrance. In vitro study showed that the overexpression of four key CCDC141 variants in HEK293 cells delayed cell migration, 72% in p.Ser55Cys (p=0.04), 66% in p.Gln507His (p=0.04), 65% in p.Asp767Asn (p=0.02), and 83% in p.Ala1073Thr (p=0.01), when compared to WT (100%). Moreover, WT-overexpressed cells increased the rate of cell migration when compared to non-transfected cells (100% vs 65%, p=0.005), reaffirming that CCDC141 has a role in cell migration. In conclusion, heterozygous deficiency of CCDC141, previously reported to cause IHH, can cause self-limited DP due to abnormal GnRH migration during foetal development.

scholarly journals Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Tansit Saengkaew ◽  
Gerard Ruiz-Babot ◽  
Alessia David ◽  
Alessandra Mancini ◽  
Katia Mariniello ◽  
...  
Keyword(s):  
Cell Migration ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Coiled Coil ◽  
Hek293 Cells ◽  
Delayed Puberty ◽  
Acetylated Tubulin ◽  
Whole Exome

AbstractDevelopmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.

scholarly journals Olfactory and vomeronasal innervation of the olfactory bulbs are not essential for GnRH-1 neuronal migration to the brain

2017 ◽  
Author(s):  
Ed Zandro Taroc ◽  
Aparna Prasad ◽  
Jennifer M. Lin ◽  
Paolo E. Forni
Keyword(s):  
Cell Migration ◽  
Embryonic Development ◽  
Sensory Neurons ◽  
Neuronal Migration ◽  
Hypogonadotropic Hypogonadism ◽  
Gonadotropin Releasing Hormone ◽  
Olfactory Bulbs ◽  
The Brain ◽  
Olfactory Pit ◽  
Vomeronasal Sensory Neurons

AbstractGonadotropin releasing hormone-1 (GnRH-1) neurons migrate from the developing olfactory pit into the hypothalamus during embryonic development. Migration of the GnRH-1 neurons is required for mammalian reproduction as these cells control release of gonadotropins from the anterior pituitary gland. Disturbances in GnRH-1 cell migration, GnRH-1 synthesis, secretion or signaling lead to varying degrees of hypogonadotropic hypogonadism (HH), which impairs pubertal onset and fertility. HH associated with congenital olfactory defects is clinically defined as Kallmann Syndrome (KS).The association of olfactory defects with HH in KS suggested potential direct relationship between defective olfactory axonal routing, lack of olfactory bulbs and aberrant GnRH-1 cell migration. However, it has never been experimentally proven that the formation of axonal connections of the olfactory and vomeronasal neurons to their functional targets are necessary for the migration GnRH-1 neurons to the hypothalamus. Loss-of-function of the Arx-1 homeobox gene leads to the lack of proper formation of the olfactory bulbs with abnormal axonal termination of olfactory sensory neurons (Yoshihara et al., 2005). We exploited the Arx-1null mouse line to investigate the role of the olfactory system (olfactory/vomeronasal fibers and OBs) in controlling GnRH-1 migration to the hypothalamus. Our data proves that correct development of the OBs, and axonal connection of the olfactory and vomeronasal sensory neurons to the forebrain are not needed for GnRH-1 neuronal migration. Moreover, we prove that the terminal nerve, which forms the GnRH-1 migratory scaffold, follows different guidance cues and differs in its genetic expression from olfactory and vomeronasal sensory neurons.Significance StatementGonadotropin Releasing Hormone-1 (GnRH-1) neurons control the reproductive axis of vertebrates. During embryonic development, these neurons migrate from the olfactory pit to the hypothalamus. GnRH-1 cell migration is commonly believed to take place along the olfactory axons. Our work reveals that correct olfactory bulb development and targeting of the olfactory and vomeronasal sensory neurons to the brain are not required for this migration. Our work challenges the idea that GnRH-1 neuronal migration to the hypothalamus relies on correct routing of the olfactory and vomeronasal sensory neurons. We provide a new basis for interpreting genetic correlations between anosmia, lack of olfactory bulbs, and hypogonadotropic hypogonadism in Kallmann Syndrome.

Mutations in HS6ST1 are causal in self-limited delayed puberty as well as idiopathic hypogonadotropic hypogonadism

2015 ◽  
Author(s):  
Sasha Howard ◽  
Ariel Poliandri ◽  
Helen Storr ◽  
Louise Metherell ◽  
Claudia Cabrera ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Idiopathic Hypogonadotropic Hypogonadism

Mutations in IGSF10 cause self-limited delayed puberty, via disturbance of GnRH neuronal migration

2015 ◽  
Author(s):  
Sasha Howard ◽  
Leo Guasti ◽  
Gerard Ruiz-Babot ◽  
Alessandra Mancini ◽  
Alessia David ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Delayed Puberty

scholarly journals Unusual phenotypes in patients with a pathogenic germline variant in DICER1

2021 ◽  
Author(s):  
Kateryna Venger ◽  
Miriam Elbracht ◽  
Julia Carlens ◽  
Peter Deutz ◽  
Felix Zeppernick ◽  
...  
Keyword(s):  
Wilms Tumor ◽  
Pleuropulmonary Blastoma ◽  
Global Developmental Delay ◽  
Facial Dysmorphism ◽  
Compound Heterozygous ◽  
Incomplete Penetrance ◽  
Developmental Abnormalities ◽  
Lung Cysts ◽  
Developmental Features ◽  
Skeletal Findings

AbstractPathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.

Development of a Strain of Rabbits with Congenital Simple Nonsyndromic Coronal Suture Synostosis Part I: Breeding Demographics, Inheritance Pattern, and Craniofacial Anomalies

1994 ◽  
Vol 31 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Mark P. Mooney ◽  
H. Losken Wolfgang ◽  
Michael I. Siegel ◽  
Janice F. Lalikos ◽  
Albert Losken ◽  
...  
Keyword(s):  
Litter Size ◽  
Rabbit Model ◽  
Pedigree Analysis ◽  
Human Populations ◽  
Incomplete Penetrance ◽  
Coronal Suture ◽  
Inheritance Pattern ◽  
Average Litter Size ◽  
Midfacial Hypoplasia ◽  
Congenital Condition

The lack of an animal model of congenital coronal suture (CS) synostosis has prompted the widespread use of an experimental rabbit model using adhesive Immobilization of the CS. Such postnatal models have helped make significant scientific contributions but may still not fully represent all aspects of the human congenital condition. In the March 1993 issue of The Cleft Palate-Craniofacial Journal we reported a female rabbit born in our laboratory with complete bilateral CS synostosis. This follow-up study presents our attempts to breed this animal and establish a strain of cranlosynostotic rabbits. To date, we have accomplished 10 back- and intercrosses with these animals and have produced a total of 71 live offspring; 10 animals exhibited complete nonsyndromic unilateral (plagiocephalic) or bilateral (brachycephalic) CS synostotic deformities at birth, and 19 animals exhibited partial CS synostosis that showed more than 75% growth retardation across the CS (well below the 95% confidence interval for normals). Results revealed that gestational time and litter size averages were consistent with those reported for the strain, although the average litter size decreased with increased inbreeding. By 1.5 weeks of age the completely synostosed animals already exhibited brachycephalic cranial vaults and midfacial hypoplasia compared to unaffected siblings. Initial pedigree analysis suggested an autosomal dominant inheritance pattern with incomplete penetrance and variable expressivity. The development of such a congenital rabbit model may prove useful In helping to understand the etiopathogenesis of this condition In human populations.

Delayed Puberty

2020 ◽  
Author(s):  
Amanda French
Keyword(s):  
Pubertal Timing ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Disease Process ◽  
Optimal Growth ◽  
Underlying Disease ◽  
Delayed Puberty ◽  
Hypergonadotropic Hypogonadism ◽  
Pubertal Delay ◽  
Constitutional Delay

Although common, delayed puberty can be distressing to patients and families.   Careful assessment is necessary to ensure appropriate physical and social development in patients that require intervention to reach pubertal milestones and achieve optimal growth.  Most pubertal delay is from lack of activation of the hypothalamic-pituitary-gonadal axis which then results in a functional or physiologic GnRH deficiency.  The delay may be temporary or permanent.  Constitutional delay (CDGP), also referred to as self-limited delayed puberty (DP), describes children on the extreme end of normal pubertal timing and is the most common cause of delayed puberty, representing about one third of cases.  Hypergonadotropic hypogonadism (primary hypogonadism) results from a failure of the gonad itself, and hypogonadotropic hypogonadism (secondary hypogonadism) results from a failure of the hypothalamic-pituitary axis, which is usually caused by another process, often systemic.  Diagnosis is based on history and examination.  Treatment is based on the underlying cause of pubertal delay and may include hormone replacement.  Involving a pediatric endocrinologist should be considered.  Appropriate counseling and ongoing support are important for all patients and families, regardless of underlying disease process.   This review contains 4 figures, 4 tables, and 32 references. Keywords: puberty, delayed puberty, hypogonadism, hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, menarche, thelarche, constitutional delay and growth in puberty, Turner syndrome

Pineal physiology and pathophysiology, including pineal tumours

2011 ◽  
pp. 267-272
Author(s):  
Anna Aulinas ◽  
Cristina Colom ◽  
Susan M. Webb
Keyword(s):  
Pineal Gland ◽  
Suprachiasmatic Nucleus ◽  
Third Ventricle ◽  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Thoracic Spinal ◽  
Neural Input ◽  
Cervical Ganglia ◽  
Upper Thoracic ◽  
Parenchymal Cells

The pineal gland is innervated mainly by sympathetic nerve fibres that inform the gland of the prevailing light-dark cycle and acts as a neuroendocrine transducer. The gland is located behind the third ventricle in the centre of the brain and is a highly vascular organ formed by neuroglial cells and parenchymal cells or pinealocytes. The latter synthesize melatonin as well as other indoleamines and peptides. The main pineal hormone melatonin (N-acetyl-5-methoxytryp-tamine) exhibits an endogenous circadian rhythm, reflecting signals originating in the suprachiasmatic nucleus; environmental lighting entrains the rhythm, by altering its timing. Independently of sleep, pineal melatonin is inhibited by light and stimulated during darkness, thanks to the neural input by a multisynaptic pathway that connects the retina, through the suprachiasmatic nucleus of the hypothalamus, preganglionic neurons in the upper thoracic spinal cord and postganglionic sympathetic fibres from the superior cervical ganglia, with the pineal gland. Melatonin deficiency may produce sleeping disorders, behavioural problems, or be associated with precocious or delayed puberty in children, while chronically elevated melatonin has been observed in some cases of hypogonadotropic hypogonadism (1, 2).

Kisspeptin-54 accurately identifies hypothalamic GnRH neuronal dysfunction in men with congenital hypogonadotropic hypogonadism

2020 ◽  
Author(s):  
Ali Abbara ◽  
Pei Chia Eng ◽  
Maria Phylactou ◽  
Sophie A. Clarke ◽  
Edouard Mills ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Hypogonadotropic Hypogonadism ◽  
Neuronal Function ◽  
Specific Test ◽  
Healthy Men ◽  
Pituitary Dysfunction ◽  
Pathogenic Variants ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Gnrh Release ◽  
Hypothalamic Function

Background: Hypogonadotropic hypogonadism is hypogonadism due to either hypothalamic or pituitary dysfunction. Whilst gonadotropin releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH-release and thus could be used to specifically interrogate hypothalamic function. Congenital Hypogonadotropic Hypogonadism (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration of function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. Methods: Men with CHH (n=21) and healthy eugonadal men (n=21) received an intravenous bolus of either GnRH (100mcg), or KP54 (6.4nmol/kg), on two occasions, and were monitored for 6hrs after administration of each neuropeptide. Results: Maximal LH-rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; P<0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (auROC curve KP54: 1.0, 95%CI 1.0-1.0; GnRH: 0.88, 95%CI 0.76-0.99). Indeed, all CHH men had an LH-rise <2.0 iU/L following KP54, whereas all healthy men had an LH-rise >4.0 iU/L. Anosmic men with CHH (i.e. Kallmann syndrome) had even lower LH-rises after KP54 than did normosmic men with CHH (P=0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH-rises after KP54 than other men with CHH (P=0.035). Conclusion: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with congenital hypogonadotropic hypogonadism.

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