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Genes May 2024Bones and teeth represent a common finding in ancient DNA studies and in forensic casework, even after a long burial. Genetic typing is the gold standard for the...
Bones and teeth represent a common finding in ancient DNA studies and in forensic casework, even after a long burial. Genetic typing is the gold standard for the personal identification of skeletal remains, but there are two main factors involved in the successful DNA typing of such samples: (1) the set-up of an efficient DNA extraction method; (2) the identification of the most suitable skeletal element for the downstream genetic analyses. In this paper, a protocol based on the processing of 0.5 g of bone powder decalcified using NaEDTA proved to be suitable for a semi-automated DNA extraction workflow using the Maxwell FSC DNA IQ™ Casework Kit (Promega, Madison, WI, USA). The performance of this method in terms of DNA recovery and quality was compared with a full demineralisation extraction protocol based on Qiagen technology and kits. No statistically significant differences were scored according to the DNA recovery and DNA degradation index (-values ≥ 0.176; r ≥ 0.907). This new DNA extraction protocol was applied to 88 bone samples (41 femurs, 19 petrous bones, 12 metacarpals and 16 molars) allegedly belonging to 27 World War II Italian soldiers found in a mass grave on the isle of Cres (Croatia). The results of the qPCR performed by the Quantifiler Human DNA Quantification kit showed values above the lowest Limit of Quantification (lLOQ; 23 pg/µL) for all petrous bones, whereas other bone types showed, in most cases, lower amounts of DNA. Replicate STR-CE analyses showed successful typing (that is, >12 markers) in all tests on the petrous bones, followed by the metacarpals (83.3%), femurs (52.2%) and teeth (20.0%). Full profiles (22/22 autosomal markers) were achieved mainly in the petrous bones (84.2%), followed by the metacarpals (41.7%). Stochastic amplification artefacts such as drop-outs or drop-ins occurred with a frequency of 1.9% in the petrous bones, whereas they were higher when the DNA recovered from other bone elements was amplified (up to 13.9% in the femurs). Overall, the results of this study confirm that petrous bone outperforms other bone elements in terms of the quantity and quality of the recovered DNA; for this reason, if available, it should always be preferred for genetic testing. In addition, our results highlight the need for accurate planning of the DVI operation, which should be carried out by a multi-disciplinary team, and the tricky issue of identifying other suitable skeletal elements for genetic testing. Overall, the results presented in this paper support the need to adopt preanalytical strategies positively related to the successful genetic testing of aged skeletal remains in order to reduce costs and the time of analysis.
Topics: Humans; Bone and Bones; World War II; DNA Fingerprinting; Forensic Genetics; Microsatellite Repeats; DNA; DNA, Ancient
PubMed: 38927608
DOI: 10.3390/genes15060672 -
Genes May 2024Landscapes are consistently under pressure from human-induced ecological change, often resulting in shifting species distributions. For some species, changing the...
Landscapes are consistently under pressure from human-induced ecological change, often resulting in shifting species distributions. For some species, changing the geographical breadth of their niche space results in matching range shifts to regions other than those in which they are formally found. In this study, we employ a population genomics approach to assess potential conservation issues arising from purported range expansions into the south Texas Brush Country of two sister species of ducks: mottled () and Mexican () ducks. Specifically, despite being non-migratory, both species are increasingly being recorded outside their formal ranges, with the northeastward and westward expansions of Mexican and mottled ducks, respectively, perhaps resulting in secondary contact today. We assessed genetic ancestry using thousands of autosomal loci across the ranges of both species, as well as sampled Mexican- and mottled-like ducks from across overlapping regions of south Texas. First, we confirm that both species are indeed expanding their ranges, with genetically pure Western Gulf Coast mottled ducks confirmed as far west as La Salle county, Texas, while Mexican ducks recorded across Texas counties near the USA-Mexico border. Importantly, the first confirmed Mexican × mottled duck hybrids were found in between these regions, which likely represents a recently established contact zone that is, on average, ~100 km wide. We posit that climate- and land use-associated changes, including coastal habitat degradation coupled with increases in artificial habitats in the interior regions of Texas, are facilitating these range expansions. Consequently, continued monitoring of this recent contact event can serve to understand species' responses in the Anthropocene, but it can also be used to revise operational survey areas for mottled ducks.
Topics: Animals; Ducks; Hybridization, Genetic; Texas; Humans; Mexico
PubMed: 38927587
DOI: 10.3390/genes15060651 -
Biomedicines Jun 2024the COVID-19 pandemic has brought to light the intricate interplay between viral infections and preexisting health conditions. In the field of kidney diseases, patients...
INTRODUCTION
the COVID-19 pandemic has brought to light the intricate interplay between viral infections and preexisting health conditions. In the field of kidney diseases, patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Chronic Kidney Disease (CKD) face unique challenges when exposed to the SARS-CoV-2 virus. This study aims to evaluate whether SARS-CoV-2 virus infection impacts renal function differently in patients suffering from ADPKD and CKD when compared to patients suffering only from CKD.
MATERIALS AND METHODS
clinical data from 103 patients were collected and retrospectively analyzed. We compared the renal function of ADPKD and CKD patients at two distinct time points: before COVID-19 infection (T0) and 1 year after the infection (T1). We studied also a subpopulation of 37 patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min and affected by ADPKD and CKD.
RESULTS
clinical data were obtained from 59 (57.3%) ADPKD patients and 44 (42.7%) CKD patients. At T1, ADPKD patients had significantly higher serum creatinine levels compared to CKD patients, and a significantly lower eGFR was observed only in ADPKD patients with eGFR < 60 mL/min compared to CKD patients ( < 0.01, < 0.05; respectively). Following COVID-19 infection, ADPKD-CKD patients exhibited significantly higher variation in both median serum creatinine ( < 0.001) and median eGFR ( < 0.001) compared to CKD patients.
CONCLUSION
the interplay between COVID-19 and kidney disease is complex. In CKD patients, the relationship between COVID-19 and kidney disease progression is more established, while limited studies exist on the specific impact of COVID-19 on ADPKD patients. Current evidence does not suggest that ADPKD patients are at a higher risk of SARS-CoV-2 infection; however, in our study we showed a significant worsening of the renal function among ADPKD patients, particularly those with an eGFR < 60 mL/min, in comparison to patients with only CKD after a one-year follow-up from COVID-19 infection.
PubMed: 38927508
DOI: 10.3390/biomedicines12061301 -
Biomedicines Jun 2024Lynch syndrome is an autosomal dominant condition that leads to an increased risk of many neoplasms. In the United Kingdom, NICE recommends that patients with colorectal...
BACKGROUND
Lynch syndrome is an autosomal dominant condition that leads to an increased risk of many neoplasms. In the United Kingdom, NICE recommends that patients with colorectal and endometrial cancer should be tested for Lynch syndrome. There is conflicting evidence in the literature on the link between breast cancer and Lynch syndrome.
CASE PRESENTATION
A 54-year-old woman presented with a lump in her right breast with a background of locally advanced colorectal cancer and Lynch syndrome due to a MLH1 gene mutation. A core biopsy showed a grade 3, invasive, triple-negative NST carcinoma. The tumour was triple-negative with patchy positivity for CK14 and CK5/6. Simultaneously, a cystic skin lesion in the contralateral breast was noted, which comprised lesional cells with a proliferation of clear cells and bland basaloid cells. The lesion had evidence of sebaceous differentiation with AR, podoplanin and p63 positivity. MSH1 and PMS2 deficiency was found in the breast and skin lesions.
CONCLUSIONS
In Lynch syndrome, it is vital to be aware of the increased risk of various types of cancer. This case adds to the body of evidence of the spectrum of malignancies that can be encountered in patients with Lynch syndrome.
PubMed: 38927449
DOI: 10.3390/biomedicines12061242 -
Biomedicines May 2024The enzyme 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) is involved in the catabolism of the amino acid tyrosine in organisms such as bacteria, plants, and animals. It...
The enzyme 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) is involved in the catabolism of the amino acid tyrosine in organisms such as bacteria, plants, and animals. It catalyzes the conversion of 4-hydroxyphenylpyruvate to a homogenisate in the presence of molecular oxygen and Fe(II) as a cofactor. This enzyme represents a key step in the biosynthesis of important compounds, and its activity deficiency leads to severe, rare autosomal recessive disorders, like tyrosinemia type III and hawkinsinuria, for which no cure is currently available. The 4-HPPD C-terminal tail plays a crucial role in the enzyme catalysis/gating mechanism, ensuring the integrity of the active site for catalysis through fine regulation of the C-terminal tail conformation. However, despite growing interest in the 4-HPPD catalytic mechanism and structure, the gating mechanism remains unclear. Furthermore, the absence of the whole 3D structure makes the bioinformatic approach the only possible study to define the enzyme structure/molecular mechanism. Here, wild-type 4-HPPD and its mutants were deeply dissected by applying a comprehensive bioinformatics/evolution study, and we showed for the first time the entire molecular mechanism and regulation of the enzyme gating process, proposing the full-length 3D structure of human 4-HPPD and two novel key residues involved in the 4-HPPD C-terminal tail conformational change.
PubMed: 38927403
DOI: 10.3390/biomedicines12061196 -
Biomolecules Jun 2024Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the... (Review)
Review
Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal-protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Mining; Polyneuropathies; Portugal
PubMed: 38927056
DOI: 10.3390/biom14060652 -
Scientific Reports Jun 2024To analyse the genetic aetiology of a child with oculocutaneous albinism and to explore the effects of two mutation sites on the function of the OCA2 protein at the mRNA...
To analyse the genetic aetiology of a child with oculocutaneous albinism and to explore the effects of two mutation sites on the function of the OCA2 protein at the mRNA and protein levels via the use of recombinant carriers in vitro. Whole-exome sequencing (WES) and Sanger sequencing were used to analyse the pathogenic genes of the child and validate the mutations in the parents. pEGFP and phage vectors carrying wild-type and mutant OCA2 were constructed using the coding DNA sequence (CDS) of the whole gene-synthesized OCA2 as a template and transfected into HEK293T cells, after which expression analysis was performed. The child in this study was born with white skin, hair, eyelashes, and eyebrows and exhibited nystagmus. Genetic analysis indicated that the child carried two heterozygous mutations: c.1079C > T (p.Ser360Phe) of maternal origin and c.1095_1103delAGCACTGGC (p.Ala366_Ala368del) of paternal origin, conforming to an autosomal recessive inheritance pattern. In vitro analysis showed that the expression of the c.1079C > T (p.Ser360Phe) mutant did not significantly change at the mRNA level but did increase at the protein level, suggesting that the mutation may lead to enhanced protein stability, and the c.1095_1103delAGCACTGGC (p.Ala366_Ala368del) mutation resulted in the loss of three amino acids in exon 10, producing a truncated protein. In vitro expression analysis also revealed that the expression of the mutant gene was significantly downregulated at both the mRNA and protein levels, suggesting that the mutation can simultaneously produce truncated proteins and lead to protein degradation. This case study enriches the phenotypic spectrum of OCA2 gene disease. In vitro expression analysis confirmed that both mutations affect protein expression, providing a theoretical basis for analysing the pathogenicity of these two mutations.
Topics: Humans; HEK293 Cells; Mutation; Albinism, Oculocutaneous; Membrane Transport Proteins; Exome Sequencing; Female; Male; Pedigree; RNA, Messenger
PubMed: 38926510
DOI: 10.1038/s41598-024-64782-2 -
Molecular Genetics & Genomic Medicine Jun 2024Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It...
BACKGROUND
Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It is a leading cause of heart failure and cardiac death at a young age. Cases with neonatal onset DCM were correlated with severe clinical presentation and poor prognosis. A monogenic molecular etiology accounts for nearly half of cases.
FAMILY DESCRIPTION
Here, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency.
RESULTS
Exome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways-based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG.
CONCLUSION
Genetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre-implantation genetic diagnosis possibilities. Our study expands the case series of early-onset DCM patients with a protein-truncating variant in the TNNI3 gene by reporting three affected infant siblings.
Topics: Humans; Cardiomyopathy, Dilated; Frameshift Mutation; Female; Homozygote; Pedigree; Consanguinity; Male; Infant; Phenotype; Troponin I
PubMed: 38924380
DOI: 10.1002/mgg3.2486 -
JMIR Aging Jun 2024Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD...
BACKGROUND
Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown.
OBJECTIVE
This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD.
METHODS
Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age.
RESULTS
The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases).
CONCLUSIONS
These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.
Topics: Humans; Female; Male; Middle Aged; Frontotemporal Dementia; Smartphone; Aged; Severity of Illness Index; Proof of Concept Study; Adult; Longitudinal Studies; Neuropsychological Tests; Mobile Applications
PubMed: 38922667
DOI: 10.2196/52831 -
Disease Models & Mechanisms Jun 2024Founder mutations are disease-causing variants that occur frequently in geographically or culturally isolated groups whose shared ancestor(s) carried the pathogenic... (Review)
Review
Founder mutations are disease-causing variants that occur frequently in geographically or culturally isolated groups whose shared ancestor(s) carried the pathogenic variant. While some disease alleles may vanish from the genetic pool due to natural selection, variants with weaker effects may survive for a long time, thereby enhancing the prevalence of some rare diseases. These are predominantly autosomal recessive diseases but can also be autosomal dominant traits with late-onset or mild phenotypes. Cultural practices, such as endogamy and consanguinity, in these isolated groups lead to higher prevalence of such rare diseases compared to the rest of the population and worldwide. In this Perspective, we define population isolates and the underlying genetic mechanisms for accumulating founder mutations. We also discuss the current and potential scientific, clinical and public-health implications of studying founder mutations in population isolates around the world, with a particular focus on the Arab population.
Topics: Humans; Rare Diseases; Founder Effect; Mutation; Arab World; Arabs
PubMed: 38922202
DOI: 10.1242/dmm.050715