Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been repo...

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Autores principales:	Rahma Mkaouar, Zied Riahi, Cherine Charfeddine, Imen Chelly, Hela Boudabbous, Hamza Dallali, Crystel Bonnet, Meriem Hechmi, Soumeya Bekri, Nadia Zitouna, Lotfi Zekri, Amel Tounsi, Rym Kefi, Jihene Marrakchi, Olfa Messaoud, Ichraf Kraoua, Sonia Maalej, Ilhem Turki Ben Youssef, Ahlem Ben Hmid, Fabrice Giraudet, Sami Bouchoucha, Neji Tebib, Ghazi Besbes, Christine Petit, Ridha Mrad, Sonia Abdelhak, Mediha Trabelsi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/569f864a04af411d83938661f5680131
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spelling	oai:doaj.org-article:569f864a04af411d83938661f56801312021-12-02T20:17:17ZAlpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.1932-620310.1371/journal.pone.0258202https://doaj.org/article/569f864a04af411d83938661f56801312021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0258202https://doaj.org/toc/1932-6203Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.Rahma MkaouarZied RiahiCherine CharfeddineImen ChellyHela BoudabbousHamza DallaliCrystel BonnetMeriem HechmiSoumeya BekriNadia ZitounaLotfi ZekriAmel TounsiRym KefiJihene MarrakchiOlfa MessaoudIchraf KraouaSonia MaalejIlhem Turki Ben YoussefAhlem Ben HmidFabrice GiraudetSami BouchouchaNeji TebibGhazi BesbesChristine PetitRidha MradSonia AbdelhakMediha TrabelsiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10, p e0258202 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rahma Mkaouar Zied Riahi Cherine Charfeddine Imen Chelly Hela Boudabbous Hamza Dallali Crystel Bonnet Meriem Hechmi Soumeya Bekri Nadia Zitouna Lotfi Zekri Amel Tounsi Rym Kefi Jihene Marrakchi Olfa Messaoud Ichraf Kraoua Sonia Maalej Ilhem Turki Ben Youssef Ahlem Ben Hmid Fabrice Giraudet Sami Bouchoucha Neji Tebib Ghazi Besbes Christine Petit Ridha Mrad Sonia Abdelhak Mediha Trabelsi Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.
description	Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.
format	article
author	Rahma Mkaouar Zied Riahi Cherine Charfeddine Imen Chelly Hela Boudabbous Hamza Dallali Crystel Bonnet Meriem Hechmi Soumeya Bekri Nadia Zitouna Lotfi Zekri Amel Tounsi Rym Kefi Jihene Marrakchi Olfa Messaoud Ichraf Kraoua Sonia Maalej Ilhem Turki Ben Youssef Ahlem Ben Hmid Fabrice Giraudet Sami Bouchoucha Neji Tebib Ghazi Besbes Christine Petit Ridha Mrad Sonia Abdelhak Mediha Trabelsi
author_facet	Rahma Mkaouar Zied Riahi Cherine Charfeddine Imen Chelly Hela Boudabbous Hamza Dallali Crystel Bonnet Meriem Hechmi Soumeya Bekri Nadia Zitouna Lotfi Zekri Amel Tounsi Rym Kefi Jihene Marrakchi Olfa Messaoud Ichraf Kraoua Sonia Maalej Ilhem Turki Ben Youssef Ahlem Ben Hmid Fabrice Giraudet Sami Bouchoucha Neji Tebib Ghazi Besbes Christine Petit Ridha Mrad Sonia Abdelhak Mediha Trabelsi
author_sort	Rahma Mkaouar
title	Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.
title_short	Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.
title_full	Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.
title_fullStr	Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.
title_full_unstemmed	Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.
title_sort	alpha-mannosidosis in tunisian consanguineous families: potential involvement of variants in ghr and slc19a3 genes in the variable expressivity of cognitive impairment.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/569f864a04af411d83938661f5680131
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Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.

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