👤 Mouna Mnif

Familial hypercholesterolemia (FH) is a genetic disorder characterised by elevated plasma LDL-cholesterol, predisposing to premature atherosclerotic cardiovascular disease. Most cases follow an autosomal dominant pattern (ADH) caused by pathogenic variants in LDLR, APOB or PCSK9. In contrast, the rare autosomal recessive form (ARH) results from biallelic mutations in LDLRAP1, leading to defective LDL receptor-mediated endocytosis. Despite the high rate of consanguinity in Tunisia, LDLRAP1 variants have not yet been reported in this population. In this study, Whole Exome Sequencing of two consanguineous Tunisian families, identified distinct pathogenic variants. In the first family (FH-A), a recurrent LDLR splice-site variant (c.1845+1G>A) was detected in both heterozygous and homozygous states, consistent with an autosomal dominant inheritance pattern. In the second family (FH-B), a novel homozygous LDLRAP1 missense variant (c.161G>A; p.Gly54Asp) was identified, confirming autosomal recessive inheritance. In silico analyses using MutationTaster, DynaMut2, MUpro, DDGun, NetSurfP-2.0, ConSurf and PyMOL predicted that the p.Gly54Asp substitution destabilises the PTB domain of LDLRAP1 by disrupting key hydrogen bonds and hydrophobic interactions, thereby likely impairing LDLR internalisation. According to ACMG guidelines, this variant is classified as likely pathogenic. Clinically, ARH patients exhibited early-onset xanthomas and an unusual quadricuspid aortic valve (QAV). Targeted analysis of valvulogenesis genes (NOTCH1, GATA4, NKX2-5, TBX5, AGTR1, BMP2) revealed no co-segregating pathogenic variants, suggesting that QAV may result from embryonic LDL accumulation disrupting Notch1 signalling rather than a monogenic defect. Comparison with other ADH Tunisian families carrying the same LDLR mutation showed phenotypic variability, likely influenced by genetic modifiers, treatment response and environmental factors. These findings provide the first evidence of LDLRAP1-associated ARH in Tunisia and highlight the genetic heterogeneity of FH, emphasising the importance of integrating molecular, structural and functional analyses for accurate diagnosis, personalised management and early prevention. Show less

Circulating fatty acids (FA) have an endogenous or exogenous origin and are metabolized under the effect of many enzymes. They play crucial roles in many mechanisms: cell signaling, modulation of gene expression, etc., which leads to the hypothesis that their perturbation could be the cause of disease development. FA in erythrocytes and plasma rather than dietary FA could be used as a biomarker for many diseases. Cardiovascular disease was associated with elevated trans FA and decreased DHA and EPA. Increased arachidonic acid and decreased Docosahexaenoic Acids (DHA) were associated with Alzheimer's disease. Low Arachidonic acid and DHA are associated with neonatal morbidities and mortality. Decreased saturated fatty acids (SFA), increased monounsaturated FA (MUFA) and polyunsaturated FA (PUFA) (C18:2 n-6 and C20:3 n-6) are associated with cancer. Additionally, genetic polymorphisms in genes coding for enzymes implicated in FA metabolism are associated with disease development. FA desaturase (FADS1 and FADS2) polymorphisms are associated with Alzheimer's disease, Acute Coronary Syndrome, Autism spectrum disorder and obesity. Polymorphisms in FA elongase (ELOVL2) are associated with Alzheimer's disease, Autism spectrum disorder and obesity. FA-binding protein polymorphism is associated with dyslipidemia, type 2 diabetes, metabolic syndrome, obesity, hypertension, non-alcoholic fatty liver disease, peripheral atherosclerosis combined with type 2 diabetes and polycystic ovary syndrome. Acetyl-coenzyme A carboxylase polymorphisms are associated with diabetes, obesity and diabetic nephropathy. FA profile and genetic variants of proteins implicated in FA metabolism could be considered as disease biomarkers and may help with the prevention and management of diseases. Show less

17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) converts Δ4-androstene-3,17-dione (androstenedione) to testosterone. It is expressed almost exclusively in the testes and is essential for appropriate male sexual development. More than 70 mutations in the HSD17B3 gene that cause 17β-HSD3 deficiency and result in 46,XY Disorders of Sex Development (46,XY DSD) have been reported. This study describes three novel Tunisian cases with mutations in HSD17B3. The first patient is homozygous for the previously reported mutation p.C206X. The inheritance of this mutation seemed to be independent of consanguineous marriage, which can be explained by its high frequency in the Tunisian population. The second patient has a novel splice site mutation in intron 6 at position c.490 -6 T > C. A splicing assay revealed a complete omission of exon 7 in the resulting HSD17B3 mRNA transcript. Skipping of exon 7 in HSD17B3 is predicted to cause a frame shift in exon 8 that affects the catalytic site and results in a truncation in exon 9, leading to an inactive enzyme. The third patient is homozygous for the novel missense mutation p.K202M, representing the first mutation identified in the catalytic tetrad of 17β-HSD3. Site-directed mutagenesis and enzyme activity measurements revealed a completely abolished 17β-HSD3 activity of the p.K202M mutant, despite unaffected protein expression, compared to the wild-type enzyme. Furthermore, the present study emphasizes the importance of genetic counselling, detabooization of 46,XY DSD, and a sensitization of the Tunisian population for the risks of consanguineous marriage. Show less

17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) isoenzyme is present almost exclusively in the testes and converts delta 4 androstenedione to testosterone. Mutations in the HSD17B3 gene cause HSD17B3 deficiency and result in 46,XY Disorders of Sex Development (46,XY DSD). This study aimed to present the clinical and biochemical features of a Tunisian patient who presented a sexual ambiguity orienting to HSD17B3 deficiency and to search for a mutation in the HSD17B3 gene by DNA sequencing. Polymerase chain reaction (PCR) amplification and subsequent sequencing of all the coding exons of HSD17B3 gene were performed on genomic DNA from the patient, her family, and 50 controls. Genetic mutation analysis of the HSD17B3 gene revealed the presence of a novel homozygous nonsense mutation in the exon 9 (c.618 C>A) leading to the substitution p.C206X. The mutation p.C206X in the coding exons supports the hypothesis of HSD17B3 deficiency in our patient. The patient described in this study represented a new case of a rare form of 46,XY DSD, associated to a novel gene mutation of HSD17B3 gene. The screening of this mutation is useful for confirming the diagnosis of HSD17B3 deficiency and for prenatal diagnosis. Show less