<scp>SRD5A3‐CDG</scp>:<scp>3D</scp>structure modeling, clinical spectrum, and<scp>computer‐based</scp>dysmorphic facial recognition

Ayed, Ikhlas Ben; Ouarda, Wael; Frikha, Fakher; Kammoun, Fatma; Souissi, Amal; Said, Mariem Ben; Bouzid, Amal; Elloumi, Inés; Hamdani, Tarak M; Gharbi, Nourhene; Baklouti, Nesrine; Guirat, M.; Mejdoub, F.; Kharrat, Najla; Boujelbene, I.; Abdelhedi, Fatma; Belguith, Neila; Keskes, Leila; Gibriel, Abdullah Ahmed; Kamoun, Hassen; Triki, Chahnez; Alimi, Adel M.; Masmoudi, Saber

doi:10.1002/ajmg.a.62065

Cited by 13 publications

(3 citation statements)

References 36 publications

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“…The ALG8 enzyme is essential in N-linked glycosylation, a co-translational modification step in the ER that promotes proper protein folding [ 33 ]. Missense variants in N-linked glycosylation enzymes can result in large structural and functional changes to the protein and, as a result, affect the complete N-linked glycosylation process [ 77 ]. Defective N-linked glycosylation results in misfolded proteins subjected to degradation to prevent ER stress [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum

Boerrigter,

te Morsche,

Venselaar

et al. 2023

Genes

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Protein-truncating variants in α-1,3-glucosyltransferase (ALG8) are a risk factor for a mild cystic kidney disease phenotype. The association between these variants and liver cysts is limited. We aim to identify pathogenic ALG8 variants in our cohort of autosomal dominant polycystic liver disease (ADPLD) individuals. In order to fine-map the phenotypical spectrum of pathogenic ALG8 variant carriers, we performed targeted ALG8 screening in 478 ADPLD singletons, and exome sequencing in 48 singletons and 4 patients from two large ADPLD families. Eight novel and one previously reported pathogenic variant in ALG8 were discovered in sixteen patients. The ALG8 clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts. The presence of <5 renal cysts that do not affect renal function is common in this population. Three-dimensional homology modeling demonstrated that six variants cause a truncated ALG8 protein with abnormal functioning, and one variant is predicted to destabilize ALG8. For the seventh variant, immunostaining of the liver tissue showed a complete loss of ALG8 in the cystic cells. ALG8-associated ADPLD has a broad clinical spectrum, including the possibility of developing a small number of renal cysts. This broadens the ADPLD genotype–phenotype spectrum and narrows the gap between liver-specific ADPLD and kidney-specific ADPKD.

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Section: Discussionmentioning

confidence: 99%

Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum

Boerrigter,

te Morsche,

Venselaar

et al. 2023

Genes

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“…Various molecular diagnostic techniques such as RFLP, Sanger sequencing and microarray have been widely utilized in detecting several HL mutations ( Gibriel et al, 2019 , Chakchouk et al, 2015 ). However, addressing such complexity necessitates the use of sophisticated NGS platforms for identification of causative HL mutations rapidly and efficiently ( Souissi et al, 2021 , Ben Ayed et al, 2021 ). In this study, we investigated a consanguineous Emirati family affected with NSHL.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing, in silico and functional studies confirm the association of the GJB2 mutation p.Cys169Tyr with deafness and suggest a role for the TMEM59 gene in the hearing process

Mahfood

Chouchen

Mohamed

et al. 2021

Saudi Journal of Biological Sciences

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The development of next generation sequencing techniques has facilitated the detection of mutations at an unprecedented rate. These efficient tools have been particularly beneficial for extremely heterogeneous disorders such as autosomal recessive non-syndromic hearing loss, the most common form of genetic deafness. GJB2 mutations are the most common cause of hereditary hearing loss. Amongst them the NM_004004.5: c.506G > A (p.Cys169Tyr) mutation has been associated with varying severity of hearing loss with unclear segregation patterns. In this study, we report a large consanguineous Emirati family with severe to profound hearing loss fully segregating the GJB2 missense mutation p.Cys169Tyr. Whole exome sequencing (WES), in silico, splicing and expression analyses ruled out the implication of any other variants and confirmed the implication of the p.Cys169Tyr mutation in this deafness family. We also show preliminary murine expression analysis that suggests a link between the TMEM59 gene and the hearing process. The present study improves our understanding of the molecular pathogenesis of hearing loss. It also emphasizes the significance of combining next generation sequencing approaches and segregation analyses especially in the diagnosis of disorders characterized by complex genetic heterogeneity.

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“…For the genetic study, DNA was isolated from peripheral blood and clinical exome sequencing was performed using the TruSight™ One Sequencing Panel. Libraries were prepared and data analysis was performed as previously described ( 12 ). The generated VCF file was annotated using the VarAft application ( 13 ).…”

Section: Patient and Methodsmentioning

confidence: 99%

Case report: Functional analysis of the p.Arg507Trp variant of the PIGT gene supporting the moderate epilepsy phenotype of mutations in the C-terminal region

Ayed

Jallouli²,

Murakami³

et al. 2023

Front. Neurol.

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Pathogenic germline variants in the PIGT gene are associated with the “multiple congenital anomalies–hypotonia-seizures syndrome 3” (MCAHS3) phenotype. So far, fifty patients have been reported, most of whom suffer from intractable epilepsy. Recently, a comprehensive analysis of a cohort of 26 patients with PIGT variants has broadened the phenotypical spectrum and indicated that both p.Asn527Ser and p.Val528Met are associated with a milder epilepsy phenotype and less severe outcomes. Since all reported patients are of Caucasian/Polish origin and most harbor the same variant (p.Val528Met), the ability to draw definitive conclusions regarding the genotype–phenotype correlation remains limited. We report a new case with a homozygous variant p.Arg507Trp in the PIGT gene, detected on clinical exome sequencing. The North African patient in question displays a predominantly neurological phenotype with global developmental delay, hypotonia, brain abnormalities, and well-controlled epileptic seizures. Homozygous and heterozygous variants in codon 507 have been reported to cause PIGT deficiency without biochemical confirmation. In this study, FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the p.Arg507Trp variant leads to mildly reduced activity. Our result confirm the pathogenicity of this variant and strengthen recently reported evidence on the genotype–phenotype correlation of the PIGT variant.

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SRD5A3‐CDG:3Dstructure modeling, clinical spectrum, andcomputer‐baseddysmorphic facial recognition

Cited by 13 publications

References 36 publications

Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum

Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum

Whole exome sequencing, in silico and functional studies confirm the association of the GJB2 mutation p.Cys169Tyr with deafness and suggest a role for the TMEM59 gene in the hearing process

Case report: Functional analysis of the p.Arg507Trp variant of the PIGT gene supporting the moderate epilepsy phenotype of mutations in the C-terminal region

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