Jul 2026· International Journal of Molecular Sciences· Vol 27, pp. 6756· 0 citations· 35 references
Medicine
TL;DR
Findings support a potential link between mitochondrial dysfunction, enteric neurodegeneration, and idiopathic achalasia and rare mitochondrial-related variants may contribute to disease susceptibility in selected individuals by increasing vulnerability of inhibitory enteric neurons, although functional validation and larger studies are required.
Abstract
Idiopathic achalasia is a rare esophageal motility disorder characterized by the selective degeneration of inhibitory myenteric neurons. Its genetic basis remains poorly defined. We investigated whether rare coding variants may contribute to disease susceptibility. Exome sequencing was performed in 31 individuals with idiopathic achalasia and seven unaffected relatives. Candidate variants were prioritized using phenotype-driven filtering and assessed through in silico and structural analysis of publicly available gene expression and single-cell transcriptomic datasets. No pathogenic or likely pathogenic variants were identified in achalasia-associated genes. A gene-agnostic analysis identified two rare heterozygous missense variants in unrelated patients: AFG3L2 c.2105G>A (p.Arg702Gln) and POLG c.1760C>T (p.Pro587Leu). Both genes encode mitochondrial proteins involved in neuronal homeostasis. The variants affected conserved residues, mapped to functionally relevant protein regions, and were predicted by multiple computational approaches to affect protein stability and function. Both genes were highly expressed in esophageal tissue, with AFG3L2 showing enrichment in enteric neuronal populations. These exploratory findings support a potential link between mitochondrial dysfunction, enteric neurodegeneration, and idiopathic achalasia. Rare mitochondrial-related variants may contribute to disease susceptibility in selected individuals by increasing vulnerability of inhibitory enteric neurons, although functional validation and larger studies are required. Accordingly, our findings should be considered hypothesis-generating rather than evidence of causality.
It is demonstrated that both heterozygous MCOLN1 variants impair TRPML1 function in vitro, identifying MCOLN1 as a candidate gene for α-synucleinopathies that warrants further investigation in larger cohorts.
Chenxin Ying, Xinhui Chen, Zhidong Cen et al.· Movement Disorders· 0 citations
The molecular and functional spectrum of SLC25A4-associated disease is expanded and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.
Mazhor Aldosary, Hanan Alqudairy, Nourah Alshalan et al.· International Journal of Mol...· 0 citations
The first functional characterization of the cardiomyopathy-associated SMYD1 N101S variant identified in a child with severe infantile cardiomyopathy is provided, establishing a mechanistic link between SMYD1 dysfunction and infantile cardiomyopathy and highlighting the importance of integrating genomic and functional approaches in rare cardiovascular disease.
Marta W. Szulik, Clint Gwynn, Magnus Creed et al.· bioRxiv· 0 citations
Heterozygous pathogenic variants in the
KCNQ2
gene underlie a broad phenotypic spectrum ranging from self-limited (familial) neonatal epilepsy (SeLNE) to developmental and epileptic encephalopathy or isolated intellectual disability. The
KCNQ2
gene encodes subunits of a voltage-gated potassium channel involved in neuronal excitability, and its mutations are known to have both loss-of-function (LoF) and gain-of-function (GoF) effects, resulting in distinct neurological syndromes. The recurrent missense LoF variant
KCNQ2
p.(Arg214Trp) has been previously reported in a single family with a presumed SeLNE phenotype, without detailed adult follow-up and with additional database-reported evidence suggesting a broader phenotype associated with this recurrent variant.
Here, we report a family with two adult carriers of the heterozygous
KCNQ2
p.(Arg214Trp) variant identified through whole-exome sequencing, including long-term follow-up into late adulthood. In addition, a literature review of previously reported cases carrying the same recurrent variant was performed.
Both individuals presented with early-onset focal epilepsy with a relapsing course, characterized by prolonged seizure-free periods followed by recurrence in adulthood. The proband demonstrated transient motor regression, developmental delay, moderate intellectual disability, ataxia and fine motor impairment. The father exhibited milder cognitive impairment and additional comorbidities in later life.
These findings challenge the concept of
KCNQ2
p.(Arg214Trp) as a self-limited epilepsy-associated variant and indicate a broader phenotypic spectrum, with persistence of epilepsy and associated neurological and non-neurological comorbidities into adulthood. Our report provides new insights into adult outcomes, aiding in genetic counseling and the long-term management of affected individuals. More extensive studies with larger cohorts carrying this variant are necessary to better define the full phenotypic spectrum and to distinguish comorbidities associated with different etiological factors, including perinatal factors.
P. Christova, M. Ostrožovičová, J. Neupauerová et al.· BMC Neurology· 0 citations
WFS1‑related disorders encompass a broad phenotypic spectrum ranging from classical autosomal-recessive Wolfram syndrome to autosomal-dominant Wolfram‑like disorders. Dominant variants may disrupt endoplasmic reticulum (ER) homeostasis, calcium handling, and ER-mitochondria communication. Here, we report a Slovak male patient with a complex multisystem Wolfram‑like phenotype and identify a rare heterozygous in‑frame deletion in
WFS1
(c.2608_2619del, p.870_873del). We aimed to determine its pathogenic potential through structural modelling and functional assays.
The genetic aetiology was investigated by Sanger sequencing, WGS and MLPA. Structural consequences of the deletion were analysed using AlphaFold3 modelling of wild‑type and mutant wolframin, followed by hydrogen‑bond quantification in ChimeraX. Functional studies were performed in HeLa cells expressing wild‑type WFS1, the rare p.870_873del variant, and two pathogenic controls (p.E809K, p.P724L). ER morphology was assessed by confocal microscopy. ER stress activation was quantified using ERSE‑luciferase reporter assays, XBP1 splicing analysis, and qPCR of UPR‑related genes. Mitochondrial fusion dynamics were measured using the photoconvertible mito‑KikGR1 system.
The patient presented with early‑onset insulin‑dependent diabetes mellitus, bilateral cataracts, sensorineural hearing loss, autism spectrum disorder, paroxysmal events, and additional systemic comorbidities. Genetic analysis identified a
de novo
in‑frame deletion affecting four amino acid residues. Structural modelling showed that the deleted region contributes to a C‑terminal hydrogen‑bonding network, and its loss resulted in a significant reduction of stabilizing interactions. Although ER morphology remained preserved, cells expressing the p.870_873del variant displayed markedly reduced mitochondrial fusion, comparable to both pathogenic controls, indicating impaired ER–mitochondria crosstalk. Functional assays further demonstrated pronounced ER stress, evidenced by significantly increased ERSE‑luciferase activity, increased XBP1 splicing, upregulation of
DDIT3
(CHOP), and mild induction of
HSPA5
(BiP), consistent with activation of the unfolded protein response.
We identified a rare likely pathogenic p.870_873del WFS1 variant associated with an autosomal-dominant WFS1‑related disorder and a multisystem Wolfram‑like phenotype. Combined structural and functional evidence indicates that this variant disrupts protein stability, activates ER stress, and impairs ER–mitochondria communication, supporting its potential pathogenic role.
Silvia Borecka, A. Zahradníková, Lukáš Varga et al.· Molecular Medicine· 0 citations
More than 70% of non-obstructive azoospermia (NOA) cases remain idiopathic, and the underlying genetic causes need to be investigated. In this study, we aimed to identify genes and variants associated with the etiology of NOA. Two NOA patients from consanguineous families, with normal karyotypes and no Y-chromosome microdeletions, were selected for whole-genome sequencing (WGS). Candidate variants were validated by Sanger sequencing. Structural protein modeling and assessment of mutation-induced changes in molecular interactions were performed using SWISS-MODEL and AlphaFold. We identified a candidate homozygous missense variant (c.899C>T, p.(Ser300Phe); rs375931805) in SOX30 in one patient; this transcription factor is highly expressed in the testis. In the second patient, a homozygous missense variant (c.1472C>T, p.(Thr491Met); rs746902232) in RNF220 and a hemizygous missense variant (c.2354A>G, p.(Gln785Arg) in the X-linked AKAP4 gene were simultaneously detected. Previous studies have shown that SOX30 knockout in mice leads to meiosis I arrest and impaired spermiogenesis. AKAP4 is exclusively expressed in the testis, and missense variants have been reported in different forms of male infertility. The co-occurrence of variants in AKAP4 and RNF220 may suggest an oligogenic etiology of NOA and contribute to the phenotypic variability associated with AKAP4 variants.
Razieh Ebrahimi Askari, A. Malcher, Fateme Sefid et al.· International Journal of Mol...· 0 citations