scholarly journals Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Anne Rovelet-Lecrux ◽  
Sebastien Feuillette ◽  
Laetitia Miguel ◽  
Catherine Schramm ◽  
Ségolène Pernet ◽  
...  
Keyword(s):  
3D Structure ◽  
Hek293 Cells ◽  
Pathophysiological Mechanism ◽  
Loss Of Function ◽  
Missense Variants ◽  
Major Player ◽  
Functional Consequences ◽  
Endosomal System ◽  
The Impact ◽  
Clear Increase

AbstractThe SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.

scholarly journals Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

2021 ◽  
Author(s):  
Anne Rovelet-Lecrux ◽  
Sebastien Feuillette ◽  
Laetitia Miguel ◽  
Catherine Schramm ◽  
Segolene Pernet ◽  
...  
Keyword(s):  
Protein Structure ◽  
Alzheimer Disease ◽  
Hek293 Cells ◽  
Pathophysiological Mechanism ◽  
Loss Of Function ◽  
Missense Variants ◽  
Major Player ◽  
Functional Consequences ◽  
Sorl1 Gene ◽  
The Impact

The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of SorLA protein. An initial screening, based on the overexpression of 71 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variations (R332W, S577P, and R654W) and two maturation-competent variations (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs were associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Finally, structural analysis of the impact of missense variations on SorLA protein structure indicated that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein structure resulting from changes in the interatomic interactions.

scholarly journals SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

2020 ◽  
Vol 22 (9) ◽  
pp. 1498-1506 ◽  
Author(s):  
Eduardo Calpena ◽  
◽  
Araceli Cuellar ◽  
Krithi Bala ◽  
Sigrid M. A. Swagemakers ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Inhibitory Activity ◽  
Loss Of Function ◽  
Missense Variants ◽  
Common Polymorphism ◽  
Metopic Synostosis ◽  
Fold Enrichment ◽  
Unaffected Parent ◽  
The Impact

Abstract Purpose Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. Methods We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. Results We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10−7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. Conclusion Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

scholarly journals Increased oxidative stress tolerance of a spontaneously-occurring perR gene mutation in Streptococcus mutans UA159

2020 ◽  
Author(s):  
Jessica K. Kajfasz ◽  
Peter Zuber ◽  
Tridib Ganguly ◽  
Jacqueline Abranches ◽  
José A. Lemos
Keyword(s):  
Oxidative Stress ◽  
Streptococcus Mutans ◽  
Stress Responses ◽  
Transcriptional Repressor ◽  
Loss Of Function ◽  
Coding Region ◽  
Major Player ◽  
The Impact ◽  
Peroxide Stress

AbstractThe ability of bacteria such as the dental pathogen Streptococcus mutans to coordinate a response against damage-inducing oxidants is a critical aspect of their pathogenicity. The oxidative stress regulator SpxA1 has been proven to be a major player in the ability of S. mutans to withstand both disulfide and peroxide stresses. While studying spontaneously-occurring variants of an S. mutans ΔspxA1 strain, we serendipitously discovered that our S. mutans UA159 host strain bore a single nucleotide deletion within the coding region ofperR, resulting in a premature truncation of the encoded protein. PerR is a metal-dependent transcriptional repressor that senses and responds to peroxide stress such that loss of PerR activity results in activation of oxidative stress responses. To determine the impact of loss of PerR regulation, we obtained a UA159 isolated bearing an intact perR copy and created a clean perR deletion mutant. Our findings indicate that loss of PerR activity results in a strain that is primed to tolerate oxidative stresses in the laboratory setting. Interestingly, RNA-Seq and targeted transcriptional expression analyses reveal that PerR has a minor contribution to the ability of S. mutans to orchestrate a transcriptional response to peroxide stress. Furthermore, we detected loss-of-function perR mutations in two other commonly used laboratory strains of S. mutans suggesting that this may be not be an uncommon occurrence. This report serves as a cautionary warning regarding the so-called domestication of laboratory strains and advocates for the implementation of more stringent strain authentication practices.ImportanceA resident of the human oral biofilm, Streptococcus mutans is one of the major bacterial pathogens associated with dental caries. This report highlights a spontaneously-occurring mutation within the laboratory strain S. mutans UA159, found in the coding region of perR, a gene encoding a transcriptional repressor associated with peroxide tolerance. Though perR mutant strains of S. mutans showed a distinct growth advantage and enhanced tolerance toward H2O2, a ΔperR deletion strain showed a small number of differentially expressed genes as compared to the parent strain, suggesting few direct regulatory targets. In addition to characterizing the role of PerR in S. mutans, our findings serve as a warning to laboratory researchers regarding bacterial adaptation to in vitro growth conditions.

scholarly journals Novel Loss-of-Function Mutations in DNAH1 Displayed Different Phenotypic Spectrum in Humans and Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Ranjha Khan ◽  
Qumar Zaman ◽  
Jing Chen ◽  
Manan Khan ◽  
Ao Ma ◽  
...  
Keyword(s):  
Male Infertility ◽  
Mutant Mice ◽  
Pathophysiological Mechanism ◽  
Loss Of Function ◽  
Fibrous Sheath ◽  
Transmission Electron Microscopy Analysis ◽  
Central Pair ◽  
Recurrent Mutations ◽  
The Impact

Male infertility is a prevalent disorder distressing an estimated 70 million people worldwide. Despite continued progress in understanding the causes of male infertility, idiopathic sperm abnormalities such as multiple morphological abnormalities of sperm flagella (MMAF) still account for about 30% of male infertility. Recurrent mutations in DNAH1 have been reported to cause MMAF in various populations, but the underlying mechanism is still poorly explored. This study investigated the MMAF phenotype of two extended consanguineous Pakistani families without manifesting primary ciliary dyskinesia symptoms. The transmission electron microscopy analysis of cross-sections of microtubule doublets revealed a missing central singlet of microtubules and a disorganized fibrous sheath. SPAG6 staining, a marker generally used to check the integration of microtubules of central pair, further confirmed the disruption of central pair in the spermatozoa of patients. Thus, whole-exome sequencing (WES) was performed, and WES analysis identified two novel mutations in the DNAH1 gene that were recessively co-segregating with MMAF phenotype in both families. To mechanistically study the impact of identified mutation, we generated Dnah1 mice models to confirm the in vivo effects of identified mutations. Though Dnah1△iso1/△iso1 mutant mice represented MMAF phenotype, no significant defects were observed in the ultrastructure of mutant mice spermatozoa. Interestingly, we found DNAH1 isoform2 in Dnah1△iso1/△iso1 mutant mice that may be mediating the formation of normal ultrastructure in the absence of full-length protein. Altogether we are first reporting the possible explanation of inconsistency between mouse and human DNAH1 mutant phenotypes, which will pave the way for further understanding of the underlying pathophysiological mechanism of MMAF.

scholarly journals The Effect of Single Nucleotide Variations in the Transmembrane Domain of OATP1B1 on in vitro Functionality

2021 ◽  
Author(s):  
Wilma Kiander ◽  
Kati-Sisko Vellonen ◽  
Melina M. Malinen ◽  
Mikko Gynther ◽  
Marja Hagström ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Cellular Localization ◽  
Transmembrane Domain ◽  
Organic Anion ◽  
Hek293 Cells ◽  
Protein Abundance ◽  
Loss Of Function ◽  
Wild Type ◽  
The Impact

Abstract Purpose Organic Anion Transporting Polypeptide 1B1 (OATP1B1) mediates hepatic influx and clearance of many drugs, including statins. The SLCO1B1 gene is highly polymorphic and its function-impairing variants can predispose patients to adverse effects. The effects of rare genetic variants of SLCO1B1 are mainly unexplored. We examined the impact of eight naturally occurring rare variants and the well-known SLCO1B1 c.521C > T (V174A) variant on in vitro transport activity, cellular localization and abundance. Methods Transport of rosuvastatin and 2,7-dichlorofluorescein (DCF) in OATP1B1 expressing HEK293 cells was measured to assess changes in activity of the variants. Immunofluorescence and confocal microscopy determined the cellular localization of OATP1B1 and LC–MS/MS based quantitative targeted absolute proteomics analysis quantified the amount of OATP1B1 in crude membrane fractions. Results All studied variants, with the exception of P336R, reduced protein abundance to varying degree. V174A reduced protein abundance the most, over 90% compared to wild type. Transport function was lost in G76E, V174A, L193R and R580Q variants. R181C decreased activity significantly, while T345M and L543W retained most of wild type OATP1B1 activity. P336R showed increased activity and H575L decreased the transport of DCF significantly, but not of rosuvastatin. Decreased activity was interrelated with lower absolute protein abundance in the studied variants. Conclusions Transmembrane helices 2, 4 and 11 appear to be crucial for proper membrane localization and function of OATP1B1. Four of the studied variants were identified as loss-of-function variants and as such could make the individual harboring these variants susceptible to altered pharmacokinetics and adverse effects of substrate drugs.

scholarly journals Increased oxidative stress tolerance of a spontaneously-occurring perR gene mutation in Streptococcus mutans UA159

2021 ◽  
Author(s):  
Jessica K. Kajfasz ◽  
Peter Zuber ◽  
Tridib Ganguly ◽  
Jacqueline Abranches ◽  
José A. Lemos
Keyword(s):  
Oxidative Stress ◽  
Streptococcus Mutans ◽  
Stress Responses ◽  
Transcriptional Repressor ◽  
Loss Of Function ◽  
Coding Region ◽  
Major Player ◽  
The Impact ◽  
Peroxide Stress

The ability of bacteria such as the dental pathogen Streptococcus mutans to coordinate a response against damage-inducing oxidants is a critical aspect of their pathogenicity. The oxidative stress regulator SpxA1 has been demonstrated to be a major player in the ability of S. mutans to withstand both disulfide and peroxide stresses. While studying spontaneously-occurring variants of an S. mutans ΔspxA1 strain, we serendipitously discovered that our S. mutans UA159 host strain bore a single nucleotide deletion within the coding region of perR, resulting in a premature truncation of the encoded protein. PerR is a metal-dependent transcriptional repressor that senses and responds to peroxide stress such that loss of PerR activity results in activation of oxidative stress responses. To determine the impact of loss of PerR regulation, we obtained a UA159 isolate bearing an intact perR copy and created a clean perR deletion mutant. Our findings indicate that loss of PerR activity results in a strain that is primed to tolerate oxidative stresses in the laboratory setting. Interestingly, RNA-Seq and targeted transcriptional expression analyses reveal that PerR offers a minor contribution to the ability of S. mutans to orchestrate a transcriptional response to peroxide stress. Furthermore, we detected loss-of-function perR mutations in two other commonly used laboratory strains of S. mutans suggesting that this may be not be an uncommon occurrence. This report serves as a cautionary tale regarding the so-called domestication of laboratory strains and advocates for the implementation of more stringent strain authentication practices. Importance: A resident of the human oral biofilm, Streptococcus mutans is one of the major bacterial pathogens associated with dental caries. This report highlights a spontaneously-occurring mutation within the laboratory strain S. mutans UA159, found in the coding region of perR, a gene encoding a transcriptional repressor associated with peroxide tolerance. Though perR mutant strains of S. mutans showed a distinct growth advantage and enhanced tolerance toward H2O2, a ΔperR deletion strain showed a small number of differentially expressed genes as compared to the parent strain, suggesting few direct regulatory targets. In addition to characterizing the role of PerR in S. mutans, our findings serve as a warning to laboratory researchers regarding bacterial adaptation to in vitro growth conditions.

scholarly journals Review: Balancing Selection for Deleterious Alleles in Livestock

2021 ◽  
Vol 12 ◽  
Author(s):  
Martijn F. L. Derks ◽  
Marije Steensma
Keyword(s):  
Balancing Selection ◽  
Low Frequency ◽  
Purifying Selection ◽  
Population Level ◽  
Selection Strategy ◽  
Loss Of Function ◽  
Deleterious Alleles ◽  
Functional Consequences ◽  
Selection For ◽  
The Impact

Harmful alleles can be under balancing selection due to an interplay of artificial selection for the variant in heterozygotes and purifying selection against the variant in homozygotes. These pleiotropic variants can remain at moderate to high frequency expressing an advantage for favorable traits in heterozygotes, while harmful in homozygotes. The impact on the population and selection strength depends on the consequence of the variant both in heterozygotes and homozygotes. The deleterious phenotype expressed in homozygotes can range from early lethality to a slightly lower fitness in the population. In this review, we explore a range of causative variants under balancing selection including loss-of-function variation (i.e., frameshift, stop-gained variants) and regulatory variation (affecting gene expression). We report that harmful alleles often affect orthologous genes in different species, often influencing analogous traits. The recent discoveries are mainly driven by the increasing genomic and phenotypic resources in livestock populations. However, the low frequency and sometimes subtle effects in homozygotes prevent accurate mapping of such pleiotropic variants, which requires novel strategies to discover. After discovery, the selection strategy for deleterious variants under balancing selection is under debate, as variants can contribute to the heterosis effect in crossbred animals in various livestock species, compensating for the loss in purebred animals. Nevertheless, gene-assisted selection is a useful tool to decrease the frequency of the harmful allele in the population, if desired. Together, this review marks various deleterious variants under balancing selection and describing the functional consequences at the molecular, phenotypic, and population level, providing a resource for further study.

scholarly journals Misfolding Induced By the Mutations V1314D and F1369I Affects the Function and the Structure of the Von Willebrand A1-Domain

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1521-1521
Author(s):  
Alexander Tischer ◽  
Pranathi Madde ◽  
Laurie Moon Tasson ◽  
Matthew Auton
Keyword(s):  
Von Willebrand Factor ◽  
Flow Chamber ◽  
Hek293 Cells ◽  
Loss Of Function ◽  
Functional Features ◽  
A1 Domain ◽  
Von Willebrand ◽  
A2 Domain ◽  
The Impact ◽  
Willebrand Factor

Abstract Von Willebrand disease (VWD) is the most common inherited human bleeding disorder. It is caused by deficiencies or defects in the plasma protein von Willebrand factor (vWF). The current classification of VWD consists of six distinct types. Type 1 and 3 result in a quantitative vWF deficiency in patients while the four type 2 variants (type 2A, 2B, 2M & 2N) are caused by qualitative defects in vWF. The von Willebrand factor is a multimeric multidomain glycoprotein that is secreted into blood from vascular endothelial cells. The protein initiates platelet adhesion at sites of cardiovascular injury. In vWF three essential domains could be identified which are responsible for the interaction with platelets and subendothelial tissue. While the A1 domain is responsible for the interaction with platelets, the A3-domain interacts with collagen from the subendothelial tissue. The A2-domain contains a cleavage site for the zinc protease AdamTS13 which regulates the size and the function of the vWF multimers by cleaving the A2-domain. We have recently studied the effect of several type 2B (= gain of function, stronger interaction with platelets) and type 2M (= loss of function, weak or no interaction with platelets) mutations in the vWF A1-domain and found clear evidence that these mutations cause a misfolding of this domain resulting in either gain- or loss of function (Tischer et al. (2014) Biophys. J. Accepted article). Hence type 2M and 2B VWD are clearly protein folding disorder diseases such like Alzheimer or various Amyloidoses. However since our group has obtained the A1-domain recombinantly from E.coli, it was unclear whether indeed misfolding of A1 is occurring or whether it is the result of the expression of the proteins in bacteria. To investigate this issue we have expressed triple domains in mammalian HEK293 cells consisting of A1, A2 and A3 and harboring the type 2B mutation V1314D and the 2B mutation F1369I in the A1 domain. The impact of the mutations on the biological function was determined in shear flow-dependent assays by observing the translocation of platelets on surface-immobilized A1- or triple domain. Using high speed video microscopy we were able to obtain statistical valid parameters for platelet translocation such as mean pause times and velocities. While F1369I did not support platelet translocation at all, V1314D was found to almost immobilize platelets in the flow chamber. The triple domain constructs harboring the mutations were found to have very similar functional features as the single domain mutants. F1369I triple domain did not support platelet translocation whereas V1314D triple domain immobilized platelets in the flow chamber at all applied shear rates. Structural characterization of the single A1 domains and of the triple domains resulted in evidence for massive misfolding in the A1 domain induced by the mutations. Therefore, all attempts to understand VWD and a potential drug development are required to account for non-native conformations of the A1 domain. Disclosures No relevant conflicts of interest to declare.

scholarly journals ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

2021 ◽  
Vol 22 (5) ◽  
pp. 2689
Author(s):  
Jianmin Si ◽  
Chris Van den Haute ◽  
Evy Lobbestael ◽  
Shaun Martin ◽  
Sarah van Veen ◽  
...  
Keyword(s):  
Membrane Integrity ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Membrane Association ◽  
Loss Of Function ◽  
Atypical Form ◽  
Polyamine Transport ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
The Impact

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway

2021 ◽  
pp. 1-10
Author(s):  
Varvara Kanti ◽  
Lia Puder ◽  
Irina Jahnke ◽  
Philipp Maximilian Krabusch ◽  
Jan Kottner ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Skin Pigmentation ◽  
Gene Mutations ◽  
Continuous Treatment ◽  
Whole Body ◽  
Hair Color ◽  
Phase 2 ◽  
Loss Of Function ◽  
The Impact ◽  
Over Time

<b><i>Background and Objectives:</i></b> Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist <i>setmelanotide</i> in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with <i>setmelanotide,</i> changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. <b><i>Methods:</i></b> In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist <i>setmelanotide</i>. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. <b><i>Results:</i></b> We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of <i>setmelanotide</i> treatment. <b><i>Discussion:</i></b> <i>Setmelanotide</i> treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

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