Dataset Information

Variant Analysis of Alkaptonuria Families with Significant Founder Effect in Jordan.

ABSTRACT:

Background

Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the HGD gene, and a deficiency HGD enzyme activity results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue.

Methods

We clinically evaluated 18 alkaptonuria patients (age range, 3 to 60 years) from four unrelated families. Furthermore, 11 out of 18 alkaptonuria patients and 7 unaffected members were enrolled for molecular investigations by utilizing Sanger sequencing to identify variants of the 14 exons of HGD gene.

Results

We found that the seven patients from the 4 unrelated families carried a recurrent pathogenic missense variant (c.365C>T, p. Ala122Val) in exon 6 of HGD gene. The variant was fully segregated with the disease in affected family members while the other unaffected family members were heterozygous carriers for this variant. Additionally, the clinical features were fully predicted with alkaptonuria disorder.

Conclusion

In this study, we confirmed that the most common variants in Jordanian AKU patients was c.365C>T, p. Ala122Val in exon 6 of HGD gene. Additionally, we correlated the clinical and genetic features of AKU patients at various ages (3-60 years).

SUBMITTER: Khalil R

PROVIDER: S-EPMC8216811 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Variant Analysis of Alkaptonuria Families with Significant Founder Effect in Jordan.

Khalil Raida R Ali Dema D Mwafi Nesrin N Alsaraireh Arwa A Obeidat Loiy L Albsoul Eman E Al Sbou' Ibrahim I

BioMed research international 20210311

<h4>Background</h4>Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the <i>HGD</i> gene, and a deficiency HGD enzyme activity results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue.<h4>Methods</h4>We clinically evaluated 18 alkaptonuria patients (age range, 3 to 60 years) from four unrelated families. Furthermore, 11 out of 18 alkaptonuria patients and 7 unaffected members were enrolled for molecular invest ...[more]

PMID: 34235214

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Project description:Background & objectives Alkaptonuria (AKU) is an autosomal recessive disease wherein biallelic pathogenic variants in the homogentisate 1,2- dioxygenase (HGD) gene encoding the enzyme homogentisate 1,2 dioxygenase cause high levels of homogentisic acid (HGA) to circulate within the body leading to its deposition in connective tissues and excretion in urine. A homozygous splice donor variant (c.87+1G>A) has been identified to be the founder variant causing alkaptonuria among Narikuravars, a group of gypsies settled in Tamil Nadu. Methods Blood and urine samples of 30 homozygous splice site donor variant individuals (2 groups aged 7-20 and 21-83 yr, with 9 and 21 individuals, respectively), carriers and 30 wild-type individuals from the Narikuravars were collected during field visits after obtaining informed consent. Clinical evaluation and genetic counselling were done. The plasma and urine HGA levels were estimated by high-performance liquid chromatography. RNA was extracted from the peripheral blood and reverse transcribed. Sanger sequencing was done to check the consequence of the splice donor variant. Relative quantification of the cDNA in the three groups was done by real-time qPCR (RT-qPCR) studies using reference genes followed by Pearson's correlation analysis. Results In our cohort, among the affected alkaptonuria individuals, the minimum age for eye pigmentation detected was 23 yr. Similarly, the minimum age for back pain and any joint pain was 30 yr and 38 yr, respectively. Sequencing of the cDNA confirmed exon 2 skipping in affected individuals. In comparison to the normal individuals, the affected individuals showed reduced HGD expression. HGD relative expression showed a significant correlation (P<0.05) with mean plasma HGA levels in the younger (≤22 yr) age group but not in the older one. There was also a significant correlation (P<0.05) of reduced HGD expression with back pain in the 21-37 yr age group. Increasing age showed a positive correlation with circulating mean plasma HGA levels and a negative correlation with excreted HGA. Interpretation & conclusions As per the authors' knowledge, this is the first study to confirm the functional effect by RT-PCR of this highly prevalent founder HGD variant causing alkaptonuria in the Narikuravar community. Both plasma and urinary HGA levels correlated well with the gene expression of this variant and could serve as potential markers of AKU severity for those with this variant.

Project description:Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.

Dataset Information

Variant Analysis of Alkaptonuria Families with Significant Founder Effect in Jordan.

Background

Methods

Results

Conclusion

Publications

Variant Analysis of Alkaptonuria Families with Significant Founder Effect in Jordan.

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