🏷

Classifications

Harrison's Part

👪

Inheritance

1

X-linked recessive inheritance HP:0001419

Renpenning syndrome follows X-linked recessive inheritance and primarily affects hemizygous males.

X-linked recessive inheritance

Show evidence (1 reference)

PMID:36797465 SUPPORT Human clinical

"Renpenning syndrome (RENS1 - OMIM 309500), which is an X-linked recessive neurodevelopmental disorder caused by variants in polyglutamine-binding protein 1 (PQBP1) is reported."

This directly supports X-linked recessive inheritance and PQBP1 causality.

⚙

Pathophysiology

3

PQBP1 spliceopathy

Loss-of-function or destabilizing pathogenic PQBP1 variants disrupt transcriptional and post-transcriptional regulation of gene expression and pre-mRNA splicing, producing a spliceopathy that alters neurodevelopmental and morphogenetic gene networks, including increased expression of a non-canonical short isoform of UPF3B (UPF3B_S); the specific directional effect on mRNA binding is not established in the cited sources.

PQBP1 hgnc:9330

RNA splicing GO:0008380 ⚠ ABNORMAL mRNA processing GO:0006397 ⚠ ABNORMAL

mRNA binding GO:0003729 ⚠ ABNORMAL

Downstream

Impaired neural progenitor proliferation and differentiation PQBP1 deficiency perturbs neural progenitor cell proliferation and brain development.

Short stature Systemic PQBP1 dysfunction impairs somatic growth, resulting in short stature.

Abnormal facial shape Developmental gene dysregulation caused by PQBP1 deficiency leads to characteristic craniofacial dysmorphism.

Small testes PQBP1 deficiency affects male gonadal development, resulting in small testes.

Microphthalmia Perturbed organogenesis from PQBP1 deficiency can manifest with ocular developmental anomalies including microphthalmia.

Atrial septal defect Perturbed cardiac morphogenesis from PQBP1 deficiency can lead to congenital heart defects such as atrial septal defect.

Anal atresia Developmental dysregulation caused by pathogenic PQBP1 variants rarely includes anorectal malformation.

Show evidence (3 references)

PMID:38030819 SUPPORT BACKGROUND Human clinical

"PQBP1 encodes a protein involved in transcriptional and post-transcriptional regulation of gene expression."

This directly supports PQBP1-dependent regulation of gene expression as a core mechanism.

PMID:36797465 SUPPORT Human clinical

"Renpenning syndrome (RENS1 - OMIM 309500), which is an X-linked recessive neurodevelopmental disorder caused by variants in polyglutamine-binding protein 1 (PQBP1) is reported."

This supports PQBP1-related disease causality and the authors' characterization of Renpenning syndrome as a spliceopathy.

PMID:41507200 SUPPORT Model organism

"This Y65C substitution induces PQBP1 misfolding, which reduces PQBP1 protein levels and consequently impedes apical progenitor proliferation."

Demonstrates that pathogenic PQBP1 misfolding and reduced protein abundance contribute to loss-of-function pathology in apical progenitors.

Altered mRNA 3'-end processing and alternative polyadenylation

In addition to partial loss-of-function from protein misfolding, the pathogenic PQBP1 p.Tyr65Cys (Y65C) missense variant exerts a gain-of-function effect by enhancing interactions with core components of the mRNA 3'-end processing machinery, preserving proliferative alternative polyadenylation (APA) profiles and impeding apical-to-basal neural progenitor transition; the net directional effect on mRNA binding across PQBP1 alleles is marked abnormal rather than strictly increased or decreased.

PQBP1 hgnc:9330

mRNA 3'-end processing GO:0031124 ⚠ ABNORMAL

mRNA binding GO:0003729 ⚠ ABNORMAL

Downstream

Impaired neural progenitor proliferation and differentiation Gain-of-function preservation of proliferative alternative polyadenylation profiles impedes the transition from apical to basal neural progenitors.

Show evidence (1 reference)

PMID:41507200 SUPPORT Model organism

"Unexpectedly, the Y65C mutation also induces a gain-of-function that interferes with the transition from apical to basal progenitors by enhancing interactions with the core components of the mRNA 3' end processing machinery, thereby preserving proliferative alternative polyadenylation (APA) profiles."

Demonstrates a gain-of-function perturbation of mRNA 3'-end processing and alternative polyadenylation for the pathogenic Y65C variant.

Impaired neural progenitor proliferation and differentiation

PQBP1 loss decreases proliferation in human neural stem cells and impairs apical-to-basal progenitor transitions during brain development, providing a cellular basis for microcephaly and cognitive impairment.

neural progenitor cell CL:0011020

PQBP1 hgnc:9330

cell population proliferation GO:0008283 ↓ DECREASED neurogenesis GO:0022008 ⚠ ABNORMAL

Downstream

Microcephaly Impaired neural progenitor proliferation and apical-to-basal progenitor transition directly reduce cortical brain growth.

Intellectual disability Defective neurogenesis and progenitor transitions lead to cognitive deficits and intellectual disability.

Global developmental delay Early cortical neurodevelopmental impairment manifests clinically as global developmental delay in infancy and early childhood.

Gray matter heterotopia Perturbed cortical progenitor transition and neuronal migration during brain development can result in periventricular gray matter heterotopia.

Autism Altered neurodevelopment in PQBP1 deficiency can manifest with autism spectrum features.

Show evidence (2 references)

PMID:38030819 SUPPORT In vitro / ex vivo

"We observed a decrease of cell proliferation, as well as the deregulation of the expression of 58 genes, comprising genes encoding proteins associated with neurodegenerative diseases, playing a role in mRNA regulation or involved in innate immunity."

This directly supports reduced progenitor proliferation after PQBP1 loss.

PMID:41507200 SUPPORT Model organism

"we generated Pqbp1Y65C/Y knock-in male mice and discovered that the Y65C mutation impairs the proliferation of apical progenitors and their subsequent transition to basal progenitors, resulting in microcephaly and cognitive deficits like those observed in Renpenning syndrome patients."

This directly supports the neural progenitor mechanism linking PQBP1 dysfunction to microcephaly and cognitive impairment.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Cardiovascular 1

Atrial septal defect HP:0001631

Show evidence (1 reference)

PMID:40372223 SUPPORT Human clinical

"Auxiliary examination showed than patient 1 had atrial septal defect, nodular heterotopia in the posterior horn of the left ventricle, angiodysplasia, and low IQ."

This directly supports congenital cardiac involvement in Renpenning syndrome.

Digestive 1

Anal atresia VERY_RARE HP:0002023

Show evidence (1 reference)

PMID:41978772 SUPPORT Human clinical

"Additionally, he presented with rare anal atresia and co-occurring autism spectrum disorder (ASD)."

This directly supports anal atresia as an expanded but documented clinical feature.

Eye 1

Microphthalmia HP:0000568

Show evidence (1 reference)

PMID:40372223 SUPPORT Human clinical

"The main clinical manifestations were unusual facies (microcephaly, long narrow face, microphthalmos, superior oblique palpebral fissure, hypertelorism of inner canthus, bulbous nasal columella) and mental retardation."

This directly supports microphthalmia as part of the facial-ocular phenotype in Renpenning syndrome.

Genitourinary 1

Small testes Decreased testicular size HP:0008734

Show evidence (1 reference)

PMID:41978772 SUPPORT Human clinical

"Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual disability caused by variations in the polyglutamine-binding protein 1 (PQBP1) gene, characterized by moderate to severe intellectual disability, microcephaly, short stature, lean body, small testes, and abnormal facial features."

This directly supports small testes as part of the core male phenotype.

Head and Neck 2

Microcephaly HP:0000252

Show evidence (2 references)

PMID:41978772 SUPPORT Human clinical

"Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual disability caused by variations in the polyglutamine-binding protein 1 (PQBP1) gene, characterized by moderate to severe intellectual disability, microcephaly, short stature, lean body, small testes, and abnormal facial features."

This directly supports microcephaly as part of the core clinical syndrome.

PMID:41507200 SUPPORT Model organism

"resulting in microcephaly and cognitive deficits like those observed in Renpenning syndrome patients."

This supports a mechanistic link between PQBP1 dysfunction and microcephaly.

Abnormal facial shape VERY_FREQUENT HP:0001999

Show evidence (2 references)

PMID:41978772 SUPPORT Human clinical

"Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual disability caused by variations in the polyglutamine-binding protein 1 (PQBP1) gene, characterized by moderate to severe intellectual disability, microcephaly, short stature, lean body, small testes, and abnormal facial features."

This directly supports a facial-dysmorphism phenotype.

PMID:40372223 SUPPORT Human clinical

"Except for two fetuses, all patients had special facial features and low IQ to varying degrees."

Supports a very high frequency of characteristic facial dysmorphism (15 of 15 postnatal cases in the 17-patient series).

Nervous System 4

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:38030819 SUPPORT BACKGROUND Human clinical

"Mutations in the PQBP1 gene (polyglutamine-binding protein-1) are responsible for a syndromic X-linked form of neurodevelopmental disorder (XL-NDD) with intellectual disability (ID), named Renpenning syndrome."

This directly supports intellectual disability as the defining neurodevelopmental feature.

PMID:40372223 SUPPORT Human clinical

"Except for two fetuses, all patients had special facial features and low IQ to varying degrees."

Supports a very high frequency of intellectual disability (15 of 15 postnatal cases in the 17-patient series).

Gray matter heterotopia HP:0002282

Show evidence (1 reference)

PMID:40372223 SUPPORT Human clinical

"Auxiliary examination showed than patient 1 had atrial septal defect, nodular heterotopia in the posterior horn of the left ventricle, angiodysplasia, and low IQ."

This directly supports gray matter heterotopia in Renpenning syndrome.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:41978772 SUPPORT Human clinical

"The proband exhibited typical manifestations of Renpenning syndrome, including severe global developmental delay, microcephaly, short stature, and characteristic facial features."

This directly supports global developmental delay as a clinical manifestation.

Autism HP:0000717

Show evidence (1 reference)

PMID:41978772 SUPPORT Human clinical

"Additionally, he presented with rare anal atresia and co-occurring autism spectrum disorder (ASD)."

This directly supports autism spectrum features in the reported case.

Growth 1

Short stature HP:0004322

Show evidence (1 reference)

PMID:41978772 SUPPORT Human clinical

"Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual disability caused by variations in the polyglutamine-binding protein 1 (PQBP1) gene, characterized by moderate to severe intellectual disability, microcephaly, short stature, lean body, small testes, and abnormal facial features."

This directly supports short stature as part of the described syndrome phenotype.

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Genetic Associations

1

PQBP1 (Causal hemizygous variant)

Gene: PQBP1 hgnc:9330

Show evidence (4 references)

PMID:41978772 SUPPORT Human clinical

"Whole exome sequencing identified a hemizygous PQBP1 frameshift variant, NM_001032382.2:c.459_462delAGAG (p.Arg153fs) (VCV000010980.79), in the proband."

This directly supports PQBP1 as the causal gene and illustrates a representative pathogenic allele class.

PMID:40372223 SUPPORT Human clinical

"A hemizygous deletion, c.459_462del (p.Arg153SerfsTer41), was identified in exon 5 of the PQBP1 gene in patient 1, which was inherited from his mother by Sanger sequencing."

This directly supports hemizygous PQBP1 causality and maternal transmission in a male proband.

PMID:41507200 SUPPORT Model organism

"The missense mutation Y65C in polyglutamine-binding protein 1 (PQBP1) is associated with Renpenning syndrome, characterized by X-linked intellectual disability and microcephaly."

This supports PQBP1 missense alleles as a recognized causal class in Renpenning syndrome.

+ 1 more reference

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Medical Actions

2

Supportive care

Action: Supportive Care NCIT:C15747

Multidisciplinary supportive management addressing developmental delay, intellectual disability, growth monitoring, and organ-system complications such as congenital heart defects, ocular anomalies, or anorectal malformations.

Target Phenotypes: Intellectual disability HP:0001249 Global developmental delay HP:0001263 Atrial septal defect HP:0001631

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling and familial carrier testing by Sanger sequencing to assess maternal X-linked carrier status and recurrence risk in affected pedigrees.

Show evidence (1 reference)

PMID:41978772 SUPPORT Human clinical

"Whole exome sequencing identified a hemizygous PQBP1 frameshift variant, NM_001032382.2:c.459_462delAGAG (p.Arg153fs) (VCV000010980.79), in the proband. Sanger sequencing confirmed this variant was maternally inherited."

Supports familial segregation testing to identify maternal carrier status for X-linked genetic counseling.

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Biochemical Markers

2

Non-canonical UPF3B short isoform (UPF3B_S) mRNA expression (Elevated)

Context: Elevated mRNA expression of a non-canonical short isoform of UPF3B (UPF3B_S) in samples obtained from patients with pathogenic PQBP1 variants, particularly pronounced for truncating variants and missense variants in the C-terminal domain.

Show evidence (1 reference)

PMID:38030819 SUPPORT Human clinical

"The link between PQBP1 loss and increase of UPF3B_S expression was confirmed in mRNA obtained from patients with pathogenic variants in PQBP1, particularly pronounced for truncating variants and missense variants located in the C-terminal domain."

Establishes elevated UPF3B_S mRNA expression in patient samples with pathogenic PQBP1 variants.

Peripheral blood DNA methylation episignature (Abnormal)

Context: Distinct genome-wide DNA methylation episignature in peripheral blood associated with pathogenic PQBP1 variants, used to construct a sensitive and specific binary classification model for Renpenning syndrome.

Show evidence (1 reference)

PMID:36797465 SUPPORT Human clinical

"In this paper, preliminary data demonstrating a DNA methylation signature for Renpenning syndrome (RENS1 - OMIM 309500), which is an X-linked recessive neurodevelopmental disorder caused by variants in polyglutamine-binding protein 1 (PQBP1) is reported. The identified episignature was then..."

Demonstrates a specific DNA methylation episignature in Renpenning syndrome.

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Diagnosis

3

Whole exome sequencing

Whole-exome sequencing or targeted exome sequencing is a practical first-line method to identify pathogenic PQBP1 variants in suspected Renpenning syndrome.

Whole Exome Sequencing NCIT:C101295

Show evidence (2 references)

PMID:40372223 SUPPORT Human clinical

"Genomic DNA was extracted from the child and his family members, and Trios-whole exome sequencing (Trios-WES) was performed."

This directly supports whole-exome sequencing as a diagnostic approach for PQBP1-related Renpenning syndrome.

PMID:41978772 SUPPORT Human clinical

"Comprehensive clinical evaluation and whole exome sequencing were performed to identify the genetic basis of the clinical presentation in a 4-year-7-month-old male proband from a Chinese family."

This supports whole-exome sequencing as a practical diagnostic procedure in Renpenning syndrome.

DNA methylation analysis

Genome-wide DNA methylation analysis can identify a Renpenning-specific episignature and may help reclassify variants of uncertain significance.

DNA Methylation Analysis NCIT:C63328

Show evidence (1 reference)

PMID:36797465 SUPPORT Human clinical

"Genome-wide DNA methylation analysis has recently been adapted for clinical testing of patients with genetic neurodevelopmental disorders."

This supports DNA methylation analysis as an emerging diagnostic adjunct, although the paper frames the Renpenning episignature as preliminary.

Whole transcriptome sequencing

Transcriptome-directed RNA sequencing (RNA-seq), particularly from skin fibroblasts or peripheral blood, can detect expression or splicing outliers to resolve PQBP1 diagnoses missed by conventional genomic testing.

Whole Transcriptome Sequencing NCIT:C124261

Show evidence (1 reference)

PMID:33001864 SUPPORT Human clinical

"Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA)."

Demonstrates that transcriptome-directed RNA-seq established a molecular diagnosis of PQBP1-related Renpenning syndrome after negative conventional exome sequencing and chromosomal microarray.

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Progression

2

Congenital and infantile onset

Age: Birth to infancy

Microcephaly, craniofacial dysmorphism, ocular anomalies, congenital heart defects, and anorectal malformations are present at birth or recognized in infancy, accompanied by early global developmental delay.

Show evidence (2 references)

PMID:40372223 SUPPORT Human clinical

"The disease began in infancy, and there was no family history of related diseases."

Documents infantile onset of clinical manifestations.

PMID:40372223 SUPPORT Human clinical

"The main clinical manifestations of RS are developmental delay, long narrow face, bulbous nose, microcephaly, and may be accompanied by heterotopia of gray matter of ventricle and congenital heart disease."

Summarizes the congenital and early neurodevelopmental features of Renpenning syndrome.

Childhood and adolescent neurodevelopmental course

Age: Childhood through adolescence

Affected males exhibit persistent moderate to severe intellectual disability, postnatal growth restriction with short stature and lean habitus, and small testes.

Show evidence (1 reference)

PMID:41978772 SUPPORT Human clinical

"Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual disability caused by variations in the polyglutamine-binding protein 1 (PQBP1) gene, characterized by moderate to severe intellectual disability, microcephaly, short stature, lean body, small testes, and abnormal facial features."

Summarizes the persistent cognitive, growth, and gonadal manifestations across childhood and adolescence.

📊

Prevalence

1

Worldwide

Cases/families reported in the literature Ultra-rare

Population-based prevalence has not been established. Renpenning syndrome is an ultra-rare X-linked intellectual disability disorder documented through multiplex pedigrees and sporadic case series in the literature, including 17 cases aggregated in a 2025 clinical literature review.

Show evidence (2 references)

PMID:41978772 SUPPORT Human clinical

"Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual disability caused by variations in the polyglutamine-binding protein 1 (PQBP1) gene, characterized by moderate to severe intellectual disability, microcephaly, short stature, lean body, small testes, and abnormal facial features."

Confirms that Renpenning syndrome is a rare X-linked intellectual disability disorder.

PMID:40372223 SUPPORT Human clinical

"According to the literature search strategy set in this study, a total of 13 cases of RS were retrieved, involving 16 cases of RS patient caused by PQBP1 gene mutation (patients 2-17), including patient 1, a total of 17 cases of RS."

Documents a literature case series of 17 affected individuals.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Renpenning syndrome:

Fragile X syndrome MONDO:0010383

Overlapping Features Fragile X syndrome is a major X-linked intellectual disability condition in males that is routinely excluded by FMR1 trinucleotide repeat testing prior to multigene X-linked intellectual disability panel sequencing for genes including PQBP1.

Distinguishing Features

Exclusion of Fragile X syndrome by FMR1 trinucleotide repeat testing prior to X-linked intellectual disability gene panel sequencing
Identification of a pathogenic hemizygous PQBP1 variant rather than an FMR1 trinucleotide repeat abnormality

Show evidence (2 references)

PMID:31906484 SUPPORT Human clinical

"We have performed targeted next-generation sequencing of 82 XLID genes on 61 non-related male patients with suggestive non-syndromic XLID. These patients were initially referred to the molecular genetics laboratory to exclude Fragile X Syndrome."

Establishes Fragile X syndrome as the primary diagnostic exclusion in males evaluated for X-linked intellectual disability panel genes including PQBP1.

PMID:31906484 SUPPORT Human clinical

"All 61 patients had normal G-banded karyotype and showed normal FMR1 trinucleotide repeat numbers."

Confirms that normal FMR1 trinucleotide repeat testing distinguishes Fragile X syndrome from candidates evaluated by the 82-gene XLID panel containing PQBP1.

Non-syndromic X-linked intellectual disability MONDO:0019181

Overlapping Features Non-syndromic or unspecific X-linked intellectual disability presents primarily with intellectual disability without recognizable syndromic dysmorphic, neurological, or systemic features, overlapping with milder or less dysmorphic presentations of XLID panel genes such as PQBP1 and requiring multigene panel or exome sequencing for differentiation.

Distinguishing Features

Absence of pathogenic PQBP1 variants on X-linked intellectual disability gene panel or exome sequencing
Lack of recognizable syndromic dysmorphic, neurological, or systemic features typical of syndromic XLID

Show evidence (2 references)

PMID:31906484 SUPPORT Human clinical

"To create a cost-efficient gene panel that could be transferable to XLID diagnosis in the clinic, we selected 82 X-linked intellectual disability genes based on the available literature at the moment. The selected gene panel includes genes that can lead to either non-syndromic XLID or high..."

Establishes that PQBP1 is included on clinical multigene panels used to differentiate non-syndromic XLID from XLID genes with high phenotypic variability in males.

PMID:31906484 SUPPORT Human clinical

"Syndromic forms of ID show dysmorphic, neurological, or systemic features that are recognizable by medical geneticists. Conversely, non-syndromic or unspecific forms only show ID as a common feature although they may individually show additional clinical features."

Supports the clinical distinction between recognizable syndromic XLID and non-syndromic or unspecific XLID presentations.

{ }

Source YAML

click to show

name: Renpenning syndrome
creation_date: "2026-04-15T00:00:00Z"
description: >-
  Renpenning syndrome is an X-linked recessive neurodevelopmental disorder
  caused by pathogenic PQBP1 variants and characterized by intellectual
  disability, microcephaly, short stature, and facial dysmorphism.
category: Mendelian
parents:
- X-linked intellectual disability
- Neurodevelopmental disorder
synonyms:
- RENS1
- X-linked intellectual disability, Renpenning type
- Golabi-Ito-Hall syndrome
- Sutherland-Haan X-linked mental retardation syndrome
- Hamel cerebropalatocardiac syndrome
- Porteous syndrome
- PQBP1-related X-linked intellectual disability
disease_term:
  preferred_term: Renpenning syndrome
  term:
    id: MONDO:0010653
    label: Renpenning syndrome
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      X-linked recessive neurodevelopmental disorder characterized by
      intellectual disability, microcephaly, and global developmental delay.
    evidence:
    - reference: PMID:36797465
      reference_title: "Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Renpenning syndrome (RENS1 - OMIM 309500), which is an X-linked
        recessive neurodevelopmental disorder caused by variants in
        polyglutamine-binding protein 1 (PQBP1) is reported.
      explanation: Establishes Renpenning syndrome as an X-linked recessive neurodevelopmental disorder.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Monogenic X-linked recessive disorder caused by hemizygous pathogenic
      variants in PQBP1.
    evidence:
    - reference: PMID:36797465
      reference_title: "Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Renpenning syndrome (RENS1 - OMIM 309500), which is an X-linked
        recessive neurodevelopmental disorder caused by variants in
        polyglutamine-binding protein 1 (PQBP1) is reported.
      explanation: Confirms the monogenic X-linked recessive genetic etiology.
inheritance:
- name: X-linked recessive inheritance
  description: >-
    Renpenning syndrome follows X-linked recessive inheritance and primarily
    affects hemizygous males.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:36797465
    reference_title: "Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renpenning syndrome (RENS1 - OMIM 309500), which is an X-linked
      recessive neurodevelopmental disorder caused by variants in
      polyglutamine-binding protein 1 (PQBP1) is reported.
    explanation: This directly supports X-linked recessive inheritance and PQBP1 causality.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Population-based prevalence has not been established. Renpenning syndrome
    is an ultra-rare X-linked intellectual disability disorder documented
    through multiplex pedigrees and sporadic case series in the literature,
    including 17 cases aggregated in a 2025 clinical literature review.
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
      disability caused by variations in the polyglutamine-binding protein 1
      (PQBP1) gene, characterized by moderate to severe intellectual
      disability, microcephaly, short stature, lean body, small testes, and
      abnormal facial features.
    explanation: Confirms that Renpenning syndrome is a rare X-linked intellectual disability disorder.
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      According to the literature search strategy set in this study, a total of
      13 cases of RS were retrieved, involving 16 cases of RS patient caused by
      PQBP1 gene mutation (patients 2-17), including patient 1, a total of 17
      cases of RS.
    explanation: Documents a literature case series of 17 affected individuals.
progression:
- phase: Congenital and infantile onset
  age_range: Birth to infancy
  notes: >-
    Microcephaly, craniofacial dysmorphism, ocular anomalies, congenital heart
    defects, and anorectal malformations are present at birth or recognized in
    infancy, accompanied by early global developmental delay.
  evidence:
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease began in infancy, and there was no family history of related
      diseases.
    explanation: Documents infantile onset of clinical manifestations.
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical manifestations of RS are developmental delay, long
      narrow face, bulbous nose, microcephaly, and may be accompanied by
      heterotopia of gray matter of ventricle and congenital heart disease.
    explanation: Summarizes the congenital and early neurodevelopmental features of Renpenning syndrome.
- phase: Childhood and adolescent neurodevelopmental course
  age_range: Childhood through adolescence
  notes: >-
    Affected males exhibit persistent moderate to severe intellectual
    disability, postnatal growth restriction with short stature and lean
    habitus, and small testes.
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
      disability caused by variations in the polyglutamine-binding protein 1
      (PQBP1) gene, characterized by moderate to severe intellectual
      disability, microcephaly, short stature, lean body, small testes, and
      abnormal facial features.
    explanation: Summarizes the persistent cognitive, growth, and gonadal manifestations across childhood and adolescence.
pathophysiology:
- name: PQBP1 spliceopathy
  description: >-
    Loss-of-function or destabilizing pathogenic PQBP1 variants disrupt
    transcriptional and post-transcriptional regulation of gene expression and
    pre-mRNA splicing, producing a spliceopathy that alters neurodevelopmental
    and morphogenetic gene networks, including increased expression of a
    non-canonical short isoform of UPF3B (UPF3B_S); the specific directional
    effect on mRNA binding is not established in the cited sources.
  genes:
  - preferred_term: PQBP1
    term:
      id: hgnc:9330
      label: PQBP1
  molecular_functions:
  - preferred_term: mRNA binding
    modifier: ABNORMAL
    term:
      id: GO:0003729
      label: mRNA binding
  biological_processes:
  - preferred_term: RNA splicing
    modifier: ABNORMAL
    term:
      id: GO:0008380
      label: RNA splicing
  - preferred_term: mRNA processing
    modifier: ABNORMAL
    term:
      id: GO:0006397
      label: mRNA processing
  evidence:
  - reference: PMID:38030819
    reference_title: "Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      PQBP1 encodes a protein involved in transcriptional and
      post-transcriptional regulation of gene expression.
    explanation: This directly supports PQBP1-dependent regulation of gene expression as a core mechanism.
  - reference: PMID:36797465
    reference_title: "Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renpenning syndrome (RENS1 - OMIM 309500), which is an X-linked
      recessive neurodevelopmental disorder caused by variants in
      polyglutamine-binding protein 1 (PQBP1) is reported.
    explanation: This supports PQBP1-related disease causality and the authors' characterization of Renpenning syndrome as a spliceopathy.
  - reference: PMID:41507200
    reference_title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This Y65C substitution induces PQBP1 misfolding, which reduces PQBP1
      protein levels and consequently impedes apical progenitor proliferation.
    explanation: Demonstrates that pathogenic PQBP1 misfolding and reduced protein abundance contribute to loss-of-function pathology in apical progenitors.
  downstream:
  - target: Impaired neural progenitor proliferation and differentiation
    causal_link_type: DIRECT
    description: PQBP1 deficiency perturbs neural progenitor cell proliferation and brain development.
    evidence:
    - reference: PMID:38030819
      reference_title: "Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We observed a decrease of cell proliferation, as well as the
        deregulation of the expression of 58 genes, comprising genes encoding
        proteins associated with neurodegenerative diseases, playing a role in
        mRNA regulation or involved in innate immunity.
      explanation: Links PQBP1 loss and transcriptomic dysregulation directly to decreased neural stem cell proliferation.
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Systemic PQBP1 dysfunction impairs somatic growth, resulting in short stature.
    evidence:
    - reference: PMID:41978772
      reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
        disability caused by variations in the polyglutamine-binding protein 1
        (PQBP1) gene, characterized by moderate to severe intellectual
        disability, microcephaly, short stature, lean body, small testes, and
        abnormal facial features.
      explanation: Connects pathogenic PQBP1 variants to short stature as a core clinical manifestation.
  - target: Abnormal facial shape
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Developmental gene dysregulation caused by PQBP1 deficiency leads to characteristic craniofacial dysmorphism.
    evidence:
    - reference: PMID:41978772
      reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
        disability caused by variations in the polyglutamine-binding protein 1
        (PQBP1) gene, characterized by moderate to severe intellectual
        disability, microcephaly, short stature, lean body, small testes, and
        abnormal facial features.
      explanation: Connects pathogenic PQBP1 variants to characteristic facial dysmorphism.
  - target: Small testes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: PQBP1 deficiency affects male gonadal development, resulting in small testes.
    evidence:
    - reference: PMID:41978772
      reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
        disability caused by variations in the polyglutamine-binding protein 1
        (PQBP1) gene, characterized by moderate to severe intellectual
        disability, microcephaly, short stature, lean body, small testes, and
        abnormal facial features.
      explanation: Connects pathogenic PQBP1 variants to small testes in affected males.
  - target: Microphthalmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Perturbed organogenesis from PQBP1 deficiency can manifest with ocular developmental anomalies including microphthalmia.
    evidence:
    - reference: PMID:40372223
      reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Except for two fetuses, all patients had special facial features and
        low IQ to varying degrees. Ten patients had abnormal development of one
        or more organs such as eyes, heart, brain, etc.
      explanation: Links PQBP1-related Renpenning syndrome to abnormal ocular organogenesis.
  - target: Atrial septal defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Perturbed cardiac morphogenesis from PQBP1 deficiency can lead to congenital heart defects such as atrial septal defect.
    evidence:
    - reference: PMID:40372223
      reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main clinical manifestations of RS are developmental delay, long
        narrow face, bulbous nose, microcephaly, and may be accompanied by
        heterotopia of gray matter of ventricle and congenital heart disease.
      explanation: Links PQBP1-related Renpenning syndrome to congenital heart disease.
  - target: Anal atresia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Developmental dysregulation caused by pathogenic PQBP1 variants rarely includes anorectal malformation.
    evidence:
    - reference: PMID:41978772
      reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This report describes the first Chinese case of Renpenning syndrome
        caused by the PQBP1 c.459_462delAGAG variant, presenting with the core
        phenotype plus anal atresia and ASD.
      explanation: Links pathogenic PQBP1 variation to anal atresia as part of the expanded clinical spectrum.
- name: Altered mRNA 3'-end processing and alternative polyadenylation
  description: >-
    In addition to partial loss-of-function from protein misfolding, the
    pathogenic PQBP1 p.Tyr65Cys (Y65C) missense variant exerts a
    gain-of-function effect by enhancing interactions with core components of
    the mRNA 3'-end processing machinery, preserving proliferative alternative
    polyadenylation (APA) profiles and impeding apical-to-basal neural
    progenitor transition; the net directional effect on mRNA binding across
    PQBP1 alleles is marked abnormal rather than strictly increased or decreased.
  genes:
  - preferred_term: PQBP1
    term:
      id: hgnc:9330
      label: PQBP1
  molecular_functions:
  - preferred_term: mRNA binding
    modifier: ABNORMAL
    term:
      id: GO:0003729
      label: mRNA binding
  biological_processes:
  - preferred_term: mRNA 3'-end processing
    modifier: ABNORMAL
    term:
      id: GO:0031124
      label: mRNA 3'-end processing
  evidence:
  - reference: PMID:41507200
    reference_title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unexpectedly, the Y65C mutation also induces a gain-of-function that
      interferes with the transition from apical to basal progenitors by
      enhancing interactions with the core components of the mRNA 3' end
      processing machinery, thereby preserving proliferative alternative
      polyadenylation (APA) profiles.
    explanation: Demonstrates a gain-of-function perturbation of mRNA 3'-end processing and alternative polyadenylation for the pathogenic Y65C variant.
  downstream:
  - target: Impaired neural progenitor proliferation and differentiation
    causal_link_type: DIRECT
    description: Gain-of-function preservation of proliferative alternative polyadenylation profiles impedes the transition from apical to basal neural progenitors.
    evidence:
    - reference: PMID:41507200
      reference_title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Unexpectedly, the Y65C mutation also induces a gain-of-function that
        interferes with the transition from apical to basal progenitors by
        enhancing interactions with the core components of the mRNA 3' end
        processing machinery, thereby preserving proliferative alternative
        polyadenylation (APA) profiles.
      explanation: Links enhanced 3'-end processing interactions and preserved proliferative APA profiles directly to impaired apical-to-basal progenitor transition.
- name: Impaired neural progenitor proliferation and differentiation
  description: >-
    PQBP1 loss decreases proliferation in human neural stem cells and impairs
    apical-to-basal progenitor transitions during brain development, providing
    a cellular basis for microcephaly and cognitive impairment.
  genes:
  - preferred_term: PQBP1
    term:
      id: hgnc:9330
      label: PQBP1
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: DECREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: neurogenesis
    modifier: ABNORMAL
    term:
      id: GO:0022008
      label: neurogenesis
  evidence:
  - reference: PMID:38030819
    reference_title: "Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We observed a decrease of cell proliferation, as well as the deregulation
      of the expression of 58 genes, comprising genes encoding proteins
      associated with neurodegenerative diseases, playing a role in mRNA
      regulation or involved in innate immunity.
    explanation: This directly supports reduced progenitor proliferation after PQBP1 loss.
  - reference: PMID:41507200
    reference_title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we generated Pqbp1Y65C/Y knock-in male mice and discovered that the Y65C
      mutation impairs the proliferation of apical progenitors and their
      subsequent transition to basal progenitors, resulting in microcephaly and
      cognitive deficits like those observed in Renpenning syndrome patients.
    explanation: This directly supports the neural progenitor mechanism linking PQBP1 dysfunction to microcephaly and cognitive impairment.
  downstream:
  - target: Microcephaly
    causal_link_type: DIRECT
    description: Impaired neural progenitor proliferation and apical-to-basal progenitor transition directly reduce cortical brain growth.
    evidence:
    - reference: PMID:41507200
      reference_title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we generated Pqbp1Y65C/Y knock-in male mice and discovered that the Y65C
        mutation impairs the proliferation of apical progenitors and their
        subsequent transition to basal progenitors, resulting in microcephaly and
        cognitive deficits like those observed in Renpenning syndrome patients.
      explanation: Demonstrates that impaired apical progenitor proliferation and basal progenitor transition cause microcephaly.
  - target: Intellectual disability
    causal_link_type: DIRECT
    description: Defective neurogenesis and progenitor transitions lead to cognitive deficits and intellectual disability.
    evidence:
    - reference: PMID:41507200
      reference_title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we generated Pqbp1Y65C/Y knock-in male mice and discovered that the Y65C
        mutation impairs the proliferation of apical progenitors and their
        subsequent transition to basal progenitors, resulting in microcephaly and
        cognitive deficits like those observed in Renpenning syndrome patients.
      explanation: Demonstrates that impaired progenitor proliferation and differentiation cause cognitive deficits.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Early cortical neurodevelopmental impairment manifests clinically as global developmental delay in infancy and early childhood.
    evidence:
    - reference: PMID:41978772
      reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The proband exhibited typical manifestations of Renpenning syndrome,
        including severe global developmental delay, microcephaly, short stature,
        and characteristic facial features.
      explanation: Supports severe global developmental delay co-occurring with microcephaly in Renpenning syndrome.
  - target: Gray matter heterotopia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Perturbed cortical progenitor transition and neuronal migration during brain development can result in periventricular gray matter heterotopia.
    evidence:
    - reference: PMID:40372223
      reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main clinical manifestations of RS are developmental delay, long
        narrow face, bulbous nose, microcephaly, and may be accompanied by
        heterotopia of gray matter of ventricle and congenital heart disease.
      explanation: Supports ventricular gray matter heterotopia as a structural brain malformation in Renpenning syndrome.
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Altered neurodevelopment in PQBP1 deficiency can manifest with autism spectrum features.
    evidence:
    - reference: PMID:41978772
      reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additionally, he presented with rare anal atresia and co-occurring
        autism spectrum disorder (ASD).
      explanation: Documents autism spectrum disorder as a neurodevelopmental manifestation in Renpenning syndrome.
genetic:
- name: PQBP1
  association: Causal hemizygous variant
  gene_term:
    preferred_term: PQBP1
    term:
      id: hgnc:9330
      label: PQBP1
  notes: >-
    Renpenning syndrome is caused by hemizygous PQBP1 variants in affected
    males; reported alleles include frameshift deletions/duplications in the
    AG-dinucleotide repeat of exon 4/5 (such as c.459_462delAGAG) and missense
    variants in the WW domain (such as p.Tyr65Cys) or C-terminal domain.
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing identified a hemizygous PQBP1 frameshift variant,
      NM_001032382.2:c.459_462delAGAG (p.Arg153fs) (VCV000010980.79), in the
      proband.
    explanation: This directly supports PQBP1 as the causal gene and illustrates a representative pathogenic allele class.
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A hemizygous deletion, c.459_462del (p.Arg153SerfsTer41), was
      identified in exon 5 of the PQBP1 gene in patient 1, which was inherited
      from his mother by Sanger sequencing.
    explanation: This directly supports hemizygous PQBP1 causality and maternal transmission in a male proband.
  - reference: PMID:41507200
    reference_title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The missense mutation Y65C in polyglutamine-binding protein 1 (PQBP1) is
      associated with Renpenning syndrome, characterized by X-linked
      intellectual disability and microcephaly.
    explanation: This supports PQBP1 missense alleles as a recognized causal class in Renpenning syndrome.
  - reference: CGGV:assertion_8128f36b-f273-49ee-bfd8-bee64b4df921-2018-11-07T110000.000Z
    reference_title: "PQBP1 / Renpenning syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PQBP1 | HGNC:9330 | Renpenning syndrome | MONDO:0010653 | XL | Definitive"
    explanation: ClinGen classifies the PQBP1-Renpenning syndrome gene-disease relationship as definitive with X-linked inheritance.
phenotypes:
- name: Intellectual disability
  category: Neurodevelopmental
  diagnostic: true
  frequency: VERY_FREQUENT
  description: >-
    Intellectual disability is the core clinical manifestation of Renpenning
    syndrome.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38030819
    reference_title: "Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Mutations in the PQBP1 gene (polyglutamine-binding protein-1) are
      responsible for a syndromic X-linked form of neurodevelopmental disorder
      (XL-NDD) with intellectual disability (ID), named Renpenning syndrome.
    explanation: This directly supports intellectual disability as the defining neurodevelopmental feature.
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Except for two fetuses, all patients had special facial features and low
      IQ to varying degrees.
    explanation: Supports a very high frequency of intellectual disability (15 of 15 postnatal cases in the 17-patient series).
- name: Microcephaly
  category: Neurologic
  diagnostic: true
  description: >-
    Microcephaly is a recurrent feature in Renpenning syndrome and a key clue
    to the diagnosis.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
      disability caused by variations in the polyglutamine-binding protein 1
      (PQBP1) gene, characterized by moderate to severe intellectual
      disability, microcephaly, short stature, lean body, small testes, and
      abnormal facial features.
    explanation: This directly supports microcephaly as part of the core clinical syndrome.
  - reference: PMID:41507200
    reference_title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      resulting in microcephaly and cognitive deficits like those observed in
      Renpenning syndrome patients.
    explanation: This supports a mechanistic link between PQBP1 dysfunction and microcephaly.
- name: Microphthalmia
  category: Ophthalmologic
  description: Ocular underdevelopment has been reported in Renpenning syndrome.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical manifestations were unusual facies (microcephaly, long
      narrow face, microphthalmos, superior oblique palpebral fissure,
      hypertelorism of inner canthus, bulbous nasal columella) and mental
      retardation.
    explanation: This directly supports microphthalmia as part of the facial-ocular phenotype in Renpenning syndrome.
- name: Small testes
  category: Genitourinary
  description: >-
    Small testes are part of the canonical male phenotype of Renpenning
    syndrome.
  phenotype_term:
    preferred_term: Decreased testicular size
    term:
      id: HP:0008734
      label: Decreased testicular size
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
      disability caused by variations in the polyglutamine-binding protein 1
      (PQBP1) gene, characterized by moderate to severe intellectual
      disability, microcephaly, short stature, lean body, small testes, and
      abnormal facial features.
    explanation: This directly supports small testes as part of the core male phenotype.
- name: Gray matter heterotopia
  category: Neurologic
  description: Gray matter heterotopia has been reported in at least one affected child.
  phenotype_term:
    preferred_term: Gray matter heterotopia
    term:
      id: HP:0002282
      label: Gray matter heterotopia
  evidence:
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Auxiliary examination showed than patient 1 had atrial septal defect,
      nodular heterotopia in the posterior horn of the left ventricle,
      angiodysplasia, and low IQ.
    explanation: This directly supports gray matter heterotopia in Renpenning syndrome.
- name: Atrial septal defect
  category: Cardiovascular
  description: Congenital heart disease has been reported in PQBP1-related disease.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Auxiliary examination showed than patient 1 had atrial septal defect,
      nodular heterotopia in the posterior horn of the left ventricle,
      angiodysplasia, and low IQ.
    explanation: This directly supports congenital cardiac involvement in Renpenning syndrome.
- name: Global developmental delay
  category: Neurodevelopmental
  description: >-
    Severe developmental delay is a common presentation in young affected
    children.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband exhibited typical manifestations of Renpenning syndrome,
      including severe global developmental delay, microcephaly, short stature,
      and characteristic facial features.
    explanation: This directly supports global developmental delay as a clinical manifestation.
- name: Short stature
  category: Growth
  description: Short stature is a recurrent growth phenotype in Renpenning syndrome.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
      disability caused by variations in the polyglutamine-binding protein 1
      (PQBP1) gene, characterized by moderate to severe intellectual
      disability, microcephaly, short stature, lean body, small testes, and
      abnormal facial features.
    explanation: This directly supports short stature as part of the described syndrome phenotype.
- name: Abnormal facial shape
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Facial dysmorphism is a recognizable component of the syndrome.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renpenning syndrome (OMIM: 309500) is a rare X-linked intellectual
      disability caused by variations in the polyglutamine-binding protein 1
      (PQBP1) gene, characterized by moderate to severe intellectual
      disability, microcephaly, short stature, lean body, small testes, and
      abnormal facial features.
    explanation: This directly supports a facial-dysmorphism phenotype.
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Except for two fetuses, all patients had special facial features and low
      IQ to varying degrees.
    explanation: Supports a very high frequency of characteristic facial dysmorphism (15 of 15 postnatal cases in the 17-patient series).
- name: Anal atresia
  category: Gastrointestinal
  frequency: VERY_RARE
  description: Anal atresia is a rare expansion of the Renpenning phenotype.
  phenotype_term:
    preferred_term: Anal atresia
    term:
      id: HP:0002023
      label: Anal atresia
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, he presented with rare anal atresia and co-occurring
      autism spectrum disorder (ASD).
    explanation: This directly supports anal atresia as an expanded but documented clinical feature.
- name: Autism
  category: Neurodevelopmental
  description: Autism spectrum features have been reported in at least one affected child.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, he presented with rare anal atresia and co-occurring
      autism spectrum disorder (ASD).
    explanation: This directly supports autism spectrum features in the reported case.
biochemical:
- name: Non-canonical UPF3B short isoform (UPF3B_S) mRNA expression
  presence: Elevated
  context: >-
    Elevated mRNA expression of a non-canonical short isoform of UPF3B
    (UPF3B_S) in samples obtained from patients with pathogenic PQBP1 variants,
    particularly pronounced for truncating variants and missense variants in the
    C-terminal domain.
  evidence:
  - reference: PMID:38030819
    reference_title: "Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The link between PQBP1 loss and increase of UPF3B_S expression was
      confirmed in mRNA obtained from patients with pathogenic variants in
      PQBP1, particularly pronounced for truncating variants and missense
      variants located in the C-terminal domain.
    explanation: Establishes elevated UPF3B_S mRNA expression in patient samples with pathogenic PQBP1 variants.
- name: Peripheral blood DNA methylation episignature
  presence: Abnormal
  context: >-
    Distinct genome-wide DNA methylation episignature in peripheral blood
    associated with pathogenic PQBP1 variants, used to construct a sensitive
    and specific binary classification model for Renpenning syndrome.
  evidence:
  - reference: PMID:36797465
    reference_title: "Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this paper, preliminary data demonstrating a DNA methylation signature
      for Renpenning syndrome (RENS1 - OMIM 309500), which is an X-linked
      recessive neurodevelopmental disorder caused by variants in
      polyglutamine-binding protein 1 (PQBP1) is reported. The identified
      episignature was then utilized to construct a highly sensitive and
      specific binary classification model.
    explanation: Demonstrates a specific DNA methylation episignature in Renpenning syndrome.
differential_diagnoses:
- name: Fragile X syndrome
  description: >-
    Fragile X syndrome is a major X-linked intellectual disability condition in
    males that is routinely excluded by FMR1 trinucleotide repeat testing prior
    to multigene X-linked intellectual disability panel sequencing for genes
    including PQBP1.
  distinguishing_features:
  - Exclusion of Fragile X syndrome by FMR1 trinucleotide repeat testing prior to X-linked intellectual disability gene panel sequencing
  - Identification of a pathogenic hemizygous PQBP1 variant rather than an FMR1 trinucleotide repeat abnormality
  disease_term:
    preferred_term: fragile X syndrome
    term:
      id: MONDO:0010383
      label: fragile X syndrome
  evidence:
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have performed targeted next-generation sequencing of 82 XLID genes on
      61 non-related male patients with suggestive non-syndromic XLID. These
      patients were initially referred to the molecular genetics laboratory to
      exclude Fragile X Syndrome.
    explanation: Establishes Fragile X syndrome as the primary diagnostic exclusion in males evaluated for X-linked intellectual disability panel genes including PQBP1.
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 61 patients had normal G-banded karyotype and showed normal FMR1
      trinucleotide repeat numbers.
    explanation: Confirms that normal FMR1 trinucleotide repeat testing distinguishes Fragile X syndrome from candidates evaluated by the 82-gene XLID panel containing PQBP1.
- name: Non-syndromic X-linked intellectual disability
  description: >-
    Non-syndromic or unspecific X-linked intellectual disability presents
    primarily with intellectual disability without recognizable syndromic
    dysmorphic, neurological, or systemic features, overlapping with milder or
    less dysmorphic presentations of XLID panel genes such as PQBP1 and
    requiring multigene panel or exome sequencing for differentiation.
  distinguishing_features:
  - Absence of pathogenic PQBP1 variants on X-linked intellectual disability gene panel or exome sequencing
  - Lack of recognizable syndromic dysmorphic, neurological, or systemic features typical of syndromic XLID
  disease_term:
    preferred_term: non-syndromic X-linked intellectual disability
    term:
      id: MONDO:0019181
      label: non-syndromic X-linked intellectual disability
  evidence:
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To create a cost-efficient gene panel that could be transferable to XLID
      diagnosis in the clinic, we selected 82 X-linked intellectual disability
      genes based on the available literature at the moment. The selected gene
      panel includes genes that can lead to either non-syndromic XLID or high
      phenotypic variability in males and candidate genes that have been
      reported in XLID but have not yet been established as XLID genes (see
      Table S1).
    explanation: Establishes that PQBP1 is included on clinical multigene panels used to differentiate non-syndromic XLID from XLID genes with high phenotypic variability in males.
  - reference: PMID:31906484
    reference_title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Syndromic forms of ID show dysmorphic, neurological, or systemic features
      that are recognizable by medical geneticists. Conversely, non-syndromic
      or unspecific forms only show ID as a common feature although they may
      individually show additional clinical features.
    explanation: Supports the clinical distinction between recognizable syndromic XLID and non-syndromic or unspecific XLID presentations.
diagnosis:
- name: Whole exome sequencing
  description: >-
    Whole-exome sequencing or targeted exome sequencing is a practical first-line
    method to identify pathogenic PQBP1 variants in suspected Renpenning syndrome.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:40372223
    reference_title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genomic DNA was extracted from the child and his family members, and
      Trios-whole exome sequencing (Trios-WES) was performed.
    explanation: This directly supports whole-exome sequencing as a diagnostic approach for PQBP1-related Renpenning syndrome.
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Comprehensive clinical evaluation and whole exome sequencing were
      performed to identify the genetic basis of the clinical presentation in
      a 4-year-7-month-old male proband from a Chinese family.
    explanation: This supports whole-exome sequencing as a practical diagnostic procedure in Renpenning syndrome.
- name: DNA methylation analysis
  description: >-
    Genome-wide DNA methylation analysis can identify a Renpenning-specific
    episignature and may help reclassify variants of uncertain significance.
  diagnosis_term:
    preferred_term: DNA Methylation Analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  evidence:
  - reference: PMID:36797465
    reference_title: "Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genome-wide DNA methylation analysis has recently been adapted for
      clinical testing of patients with genetic neurodevelopmental disorders.
    explanation: This supports DNA methylation analysis as an emerging diagnostic adjunct, although the paper frames the Renpenning episignature as preliminary.
- name: Whole transcriptome sequencing
  description: >-
    Transcriptome-directed RNA sequencing (RNA-seq), particularly from skin
    fibroblasts or peripheral blood, can detect expression or splicing outliers
    to resolve PQBP1 diagnoses missed by conventional genomic testing.
  diagnosis_term:
    preferred_term: Whole Transcriptome Sequencing
    term:
      id: NCIT:C124261
      label: Whole Transcriptome Sequencing
  evidence:
  - reference: PMID:33001864
    reference_title: "Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1),
      Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and
      CLTC-related intellectual disability, and others, all with negative
      conventional genomic testing, including ES and chromosomal microarray
      (CMA).
    explanation: Demonstrates that transcriptome-directed RNA-seq established a molecular diagnosis of PQBP1-related Renpenning syndrome after negative conventional exome sequencing and chromosomal microarray.
clinical_trials: []
datasets: []
environmental: []
treatments:
- name: Supportive care
  description: >-
    Multidisciplinary supportive management addressing developmental delay,
    intellectual disability, growth monitoring, and organ-system complications
    such as congenital heart defects, ocular anomalies, or anorectal
    malformations.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  notes: >-
    No cached reference for this entry directly describes clinical treatment or
    supportive care regimens; management is multidisciplinary and symptomatic
    according to the affected organ systems.
- name: Genetic counseling
  description: >-
    Genetic counseling and familial carrier testing by Sanger sequencing to
    assess maternal X-linked carrier status and recurrence risk in affected
    pedigrees.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41978772
    reference_title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing identified a hemizygous PQBP1 frameshift variant,
      NM_001032382.2:c.459_462delAGAG (p.Arg153fs) (VCV000010980.79), in the
      proband. Sanger sequencing confirmed this variant was maternally
      inherited.
    explanation: Supports familial segregation testing to identify maternal carrier status for X-linked genetic counseling.
references:
- reference: PMID:31906484
  title: "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability."
  findings: []
- reference: PMID:33001864
  title: "Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing."
  findings: []
- reference: PMID:36797465
  title: "Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy."
  findings: []
- reference: PMID:38030819
  title: "Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome."
  findings: []
- reference: PMID:40372223
  title: "[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review]."
  findings: []
- reference: PMID:41507200
  title: "The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects."
  findings: []
- reference: PMID:41978772
  title: "Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review."
  findings: []

📚

References & Deep Research

References

7

PMID:31906484

Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.

No top-level findings curated for this source.

PMID:33001864

Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing.

No top-level findings curated for this source.

PMID:36797465

Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy.

No top-level findings curated for this source.

PMID:38030819

Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome.

No top-level findings curated for this source.

PMID:40372223

[Clinical analysis of a child with heterotopic ventricular gray matter Renpenning syndrome caused by PQBP1 gene mutation and a literature review].

No top-level findings curated for this source.

PMID:41507200

The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects.

No top-level findings curated for this source.

PMID:41978772

Renpenning syndrome caused by the c.459_462delAGAG mutation in PQBP1: a case report and literature review.

No top-level findings curated for this source.

Deep Research

1

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Renpenning syndrome. Core disease mechanisms, molecular and cellular pathw...

Asta Scientific Corpus Retrieval 20 citations 2026-04-15T19:36:27.712809

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Renpenning syndrome. Core disease mechanisms, molecular and cellular pathw...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
Year: 2015
Venue: Expert Opinion on Orphan Drugs
URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
DOI: 10.1517/21678707.2015.1083853
PMID: 26635999
PMCID: 4643203
Citations: 37
Influential citations: 1
Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Evidence snippets:
Snippet 1 (score: 0.392) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[2] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.388) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[3] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
Year: 2012
Venue: Croatian Medical Journal
URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
DOI: 10.3325/cmj.2012.53.529
PMID: 23275318
PMCID: 3541579
Citations: 28
Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
Evidence snippets:
Snippet 1 (score: 0.375) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[4] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
Year: 2025
Venue: Scientific Reports
URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
DOI: 10.1038/s41598-025-97642-8
PMID: 40229542
PMCID: 11997208
Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
Evidence snippets:
Snippet 1 (score: 0.371) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[5] Renal ciliopathies: promising drug targets and prospects for clinical trials

Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
Year: 2023
Venue: Expert Opinion on Therapeutic Targets
URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
DOI: 10.1080/14728222.2023.2218616
PMID: 37243567
Citations: 10
Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
Evidence snippets:
Snippet 1 (score: 0.367) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

[6] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
Year: 2026
Venue: Nucleus
URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
DOI: 10.1080/19491034.2025.2611484
PMID: 41489464
PMCID: 12773485
Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
Evidence snippets:
Snippet 1 (score: 0.366) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[7] Network pharmacology analysis of molecular targets and related mechanisms of Guizhi decoction in treating of menopausal syndrome

Authors: Qian Zhang, Jingtao Liang, Ying-chuan Zhou
Year: 2022
Venue: Medicine
URL: https://www.semanticscholar.org/paper/c96933f062b544f59878ea15144ea7b93647cf4b
DOI: 10.1097/MD.0000000000029453
PMID: 35866834
PMCID: 9302318
Citations: 5
Summary: The relevant targets and mechanisms of GZD in the treatment of MPS were discussed from the perspective of network pharmacological analysis, reflecting the characteristics of multi-component, multi-target and multiple pathways, and it provides a good theoretical basis for the clinical application of GzD.
Evidence snippets:
Snippet 1 (score: 0.358) > Compared with hormone therapy, TCM had the advantages of overall adjustment and less side effects in the treatment of menopausal syndrome. But due to the complex pharmacodynamic composition of Guizhi decoction (GZD), the mechanism of TCM treating diseases was not clear. Network pharmacology could analyze drug action pathways through multi-pathway and multi-target, which provide a new direction for TCM mechanism research. The common targets of GZD and menopausal syndrome (MPS) were obtained by TCMSP and DisGeNET databases. And for the common targets, protein-protein interaction networks were established using the STRING database and analyzed by Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. (Our research does not require ethical approval). One hundred forty-six active ingredients with 283 targets were obtained from GZD by network pharmacological analysis. Besides, 230 target genes were found to have interactions with MPS, 52 of which were common targets between MPS and GZD and were predicted to be potential targets for MPS treatment of GZD. GO enrichment analysis revealed that GZD could affect 51 biological processes, 15 cellular components, and 13 molecular functions. Kyoto Encyclopedia of Genes and Genomes enrichment analysis yielded a total of 223. The pathways that are closely related to the pathogenesis of MPS are MAPK, PI3K-Akt. In this study, the relevant targets and mechanisms of GZD in the treatment of MPS were discussed from the perspective of network pharmacological analysis, reflecting the characteristics of multi-component, multi-target and multiple pathways, and it provides a good theoretical basis for the clinical application of GZD.

[8] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

Authors: W. Tulalamba, T. Janvilisri
Year: 2012
Venue: International Journal of Cell Biology
URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
DOI: 10.1155/2012/594681
PMID: 22500174
PMCID: 3303613
Citations: 93
Influential citations: 5
Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
Evidence snippets:
Snippet 1 (score: 0.356) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[9] Insights Into Cockayne Syndrome Type B: What Underlies Its Pathogenesis?

Authors: Ricardo Afonso-Reis, Cristiana R Madeira, D. Brito, C. Nóbrega
Year: 2025
Venue: Aging Cell
URL: https://www.semanticscholar.org/paper/1b86ba09359d5e2f0ff083dd037d872b4faec812
DOI: 10.1111/acel.70136
PMID: 40536083
PMCID: 12266758
Citations: 3
Summary: It is proposed that CS‐B pathogenesis arises from a combination of DNA damage accumulation, transcriptional dysregulation, and mitochondrial dysfunction, and it is argued that these molecular features influence each other, rather than acting as isolated mechanisms.
Evidence snippets:
Snippet 1 (score: 0.354) > Cockayne Syndrome complementation group B is a complex disorder with diverse underlying molecular mechanisms that contribute for its highly debilitating and multisystemic phenotype. Years of research focusing on the physiological role of ERCC6 have provided extensive knowledge regarding different processes and cellular pathways dependent on ERCC6. Most accumulated knowledge regarding ERCC6 function is related to its crucial role in TC-NER. Nevertheless, significant advances have been made associating ERCC6 with several other mechanisms that are essential for proper cell functioning. This has helped bridge the gap in the knowledge in the pathological context of Cockayne Syndrome. Currently, ERCC6 has been identified to play an important role in distinct DNA repair mechanism, responsible for tackling different type of DNA damage. These mechanisms include TC-NER, BER, and DSB repair where ERCC6 is essential for the recruitment of repair machinery, and ICL repair where ERCC6 modulates effector repair factors. Notably, ERCC6 function is not limited to DNA repair. In fact, ERCC6 is implicated in transcription by remodeling chromatin of relevant regions, modulating RNAP I and II and cooperating with transcription factors and co-factors. Additionally, mitochondrial processes such as mtDNA maintenance, mitochondrial transcription and structural organization also rely on ERCC6. The key role ERCC6 plays in all these cellular processes, highlights the importance of ERCC6 for proper cell functioning. Ultimately, ERCC6 dysfunction leads to extremely deleterious consequences to the cell, which culminates in cellular malfunction and cell death. > Premature aging is a hallmark of progeroid syndromes, such as Cockayne Syndrome. Therefore, a relation between normal aging and Cockayne syndrome pathophysiology may be established to explore the potential mechanisms driving CS progression. Considering the cellular processes ERCC6 is involved in a physiological context, in this review we have organized CS-B pathophysiology into main three molecular features. These features include DNA damage accumulation, transcriptional dysregulation and mitochondrial dysfunction. Importantly, we consider that these features do not act as isolated pathways but rather influence one another, through a mechanism interplay. This interplay has the potential to exacerbate dysfunction of affected features or induce dysfunction of an otherwise functional feature.

[10] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

Authors: Kyung-Yil Lee
Year: 2022
Venue: Cell & Bioscience
URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
DOI: 10.1186/s13578-022-00920-5
PMID: 36384812
PMCID: 9668226
Citations: 9
Influential citations: 1
Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
Evidence snippets:
Snippet 1 (score: 0.354) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[11] A review of recent studies on the pathogenesis of Systemic Sclerosis: focus on fibrosis pathways

Authors: S.A. Jimenez, F. Mendoza, S. Piera-velázquez
Year: 2025
Venue: Frontiers in Immunology
URL: https://www.semanticscholar.org/paper/885a4a3f2202767da19370ad8e55f8fa85d9a135
DOI: 10.3389/fimmu.2025.1551911
PMID: 40308583
PMCID: 12040652
Citations: 17
Influential citations: 2
Summary: Systemic Sclerosis is a systemic autoimmune disease of unknown etiology characterized by the development of frequently progressive cutaneous and internal organ fibrosis accompanied by severe vascular alterations, resulting in a wide heterogeneity in the extent and severity of clinical manifestations.
Evidence snippets:
Snippet 1 (score: 0.354) > Systemic Sclerosis (SSc) is a clinically heterogeneous systemic autoimmune disease of unknown etiology characterized by a frequently progressive fibrotic process affecting the skin and various internal organs. The fibrotic process in SSc is usually accompanied by vasculopathy of small arteries and arterioles, the presence of a chronic inflammatory process in the affected tissues, and the occurrence of humoral and cellular immune abnormalities resulting in the production of multiple autoantibodies, some with high specificity for the disease and the SSc clinical phenotype (1)(2)(3)(4). > The molecular mechanisms involved in the clinical and pathologic manifestations of the disease are highly complex, and although numerous studies have provided substantial information about its intricate picture and clarified some of its early events, the precise altered regulatory pathways involved have not been completely elucidated. However, it has been well recognized that SSc involves multiple alterations in various molecular pathways (5)(6)(7)(8)(9) that may occur simultaneously or may develop sequentially. These events include: 1) Fibroproliferative lesions of small arteries and arterioles accompanied by severe structural and functional endothelial cell alterations; 2) Severe oxidative and high reactive oxygen species; 3) Excessive and often progressive deposition of collagen and other extracellular matrix (ECM) macromolecules in skin and various internal organs; 4) Alterations of cellular and humoral immunity with the production of numerous autoantibodies, some with high disease and clinical phenotype specificity; 5) Establishment of a chronic inflammatory process in affected tissues; 6) Cellular transdifferentation resulting in the phenotypic conversion of various cell types including resting fibroblasts, endothelial cells, epithelial cells, adipocytes, and other cells into activated myofibroblasts, the cellular elements ultimately involved in the exaggerated and excessive production and accumulation of fibrotic tissue; 7) Production and release of increased levels of various cytokines and growth factors causing profibrotic and inflammatory effects; and 8) Epigenetic alterations including numerous changes mediated by non-coding RNAs.

[12] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

Authors: Hao Xiong, Jinsheng Guo
Year: 2025
Venue: Pharmaceuticals
URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
DOI: 10.3390/ph18040507
PMID: 40283943
PMCID: 12030350
Citations: 8
Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
Evidence snippets:
Snippet 1 (score: 0.353) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[13] Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

Authors: Jakub Szyller, I. Bil-Lula
Year: 2021
Venue: Oxidative Medicine and Cellular Longevity
URL: https://www.semanticscholar.org/paper/4ec4bee9f1b89cdf5a3c513d847990f3cfc18bb8
DOI: 10.1155/2021/6678457
PMID: 33603951
PMCID: 7868165
Citations: 112
Influential citations: 2
Summary: The latest research focuses on determining the role of H SPs in OS, their antioxidant activity, and the possibility of using HSPs in the treatment of I/R consequences, where reactive oxygen species play a major role.
Evidence snippets:
Snippet 1 (score: 0.352) > Heat shock proteins play a cytoprotective role under pathological conditions such as cardiovascular diseases. The knowledge about cellular and molecular mechanisms underlying ROS-mediated modulation of HSP expression can help to better understand the pathophysiology of OS, which is associated with the development of many diseases (cardiovascular, neurodegenerative, etc.). I/R injury is considered a major contributor to tissue damage in multiple clinical situations such as myocardial infarction, stroke, and organ transplantation. Oxidative damage is a key factor in the initiation of I/R. HSP expression is highly sensitive to I/R injury. > Understanding the exact mechanisms of HSP and the structure of the protein interaction network can help to better understand the pathophysiology and treatment of many diseases, as well as to develop new drugs. There is a need to understand the relationship between cell pathways-signaling, metabolism, etc. The relationships between HSP and OS discussed in this work seem to be very complicated and not yet fully understood. Data showed that modulation of HSP expression in reperfusion injuries may result in better treatment of myocardial infarction. This can also help to prepare organs for the transplantation.

[14] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
Year: 2025
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
DOI: 10.3390/ijms26062571
PMID: 40141213
PMCID: 11942187
Citations: 4
Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
Evidence snippets:
Snippet 1 (score: 0.350) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[15] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
Year: 2015
Venue: Orphanet Journal of Rare Diseases
URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
DOI: 10.1186/s13023-015-0242-9
PMID: 25874378
PMCID: 4358699
Citations: 93
Influential citations: 5
Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
Evidence snippets:
Snippet 1 (score: 0.349) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[16] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

Authors: O. Tsukamoto
Year: 2019
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
DOI: 10.3390/ijms21010226
PMID: 31905684
PMCID: 6982115
Citations: 16
Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
Evidence snippets:
Snippet 1 (score: 0.349) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[17] Molecular insights into the premature aging disease progeria

Authors: Sandra Vidak, R. Foisner
Year: 2016
Venue: Histochemistry and Cell Biology
URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
DOI: 10.1007/s00418-016-1411-1
PMID: 26847180
PMCID: 4796323
Citations: 105
Influential citations: 3
Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
Evidence snippets:
Snippet 1 (score: 0.348) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[18] Nuclear damages and oxidative stress: new perspectives for laminopathies

Authors: G. Lattanzi, S. Marmiroli, Andrea Facchini, N. Maraldi
Year: 2012
Venue: European Journal of Histochemistry : EJH
URL: https://www.semanticscholar.org/paper/8611d2c59658a5c3139c153051a0a4d8881c55ea
DOI: 10.4081/ejh.2012.e45
PMID: 23361241
PMCID: 3567764
Citations: 49
Influential citations: 3
Summary: The identification of a mechanism that accounts for accumulation of unrepairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathies patients.
Evidence snippets:
Snippet 1 (score: 0.347) > Mutations in genes encoding nuclear envelope proteins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, referred to as laminopathies. The astonishing variety of diseased phenotypes suggests that different mechanisms could be involved in the pathogenesis of laminopathies. In this review we will focus mainly on two of these pathogenic mechanisms: the nuclear damages affecting the chromatin organization, and the oxidative stress causing un-repairable DNA damages. Alteration in the nuclear profile and in chromatin organization, which are particularly impressive in systemic laminopathies whose cells undergo premature senescence, are mainly due to accumulation of unprocessed prelamin A. The toxic effect of these molecular species, which interfere with chromatin-associated proteins, transcription factors, and signaling pathways, could be reduced by drugs which reduce their farnesylation and/or stability. In particular, inhibitors of farnesyl transferase (FTIs), have been proved to be active in rescuing the altered cellular phenotype, and statins, also in association with other drugs, have been included into pilot clinical trials. The identification of a mechanism that accounts for accumulation of unrepairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathic patients.

[19] Chemotherapy and Mechanisms of Resistance in Breast Cancer

Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
Year: 2012
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
DOI: 10.5772/24629
Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
Evidence snippets:
Snippet 1 (score: 0.344) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[20] Multimarker Panels in Diabetic Kidney Disease: The Way to Improved Clinical Trial Design and Clinical Practice?

Authors: P. Perco, M. Pena, H. Heerspink, G. Mayer
Year: 2018
Venue: Kidney International Reports
URL: https://www.semanticscholar.org/paper/7a5d5fe26a543e117b4bc1adc9ef195d0469aa75
DOI: 10.1016/j.ekir.2018.12.001
PMID: 30775618
PMCID: 6365367
Citations: 23
Influential citations: 1
Summary: Evidence on the variation of DKD disease progression as well as the response to therapy is summarized and procedures to model disease pathophysiology supporting biomarker panel construction are outlined.
Evidence snippets:
Snippet 1 (score: 0.344) > The explained variability of annual eGFR loss by the biomarkers indicated by the adjusted R 2 was 15% and 34% for patients with $60 and <60 ml/ min per 1.73 m 2 , respectively, and by clinical predictors 20% and 29%, respectively. A combination of molecular and clinical predictors increased the adjusted R 2 to 35% and 64%, respectively. 41 dentifying specific molecular processes associated with a specific phenotype of DKD and biomarkers associated with these processes, based on a molecular model of DKD, can be used to characterize the progression of patients based on individual pathophysiology. Matching the molecular mode of action of drug(s) to these specific molecular processes might allow selecting a specific drug or drug combinations that prevent or reverse deregulations in identified molecular pathways and thus guide therapy. This situation mirrors the one applied in infectious diseases, in which repetitively pathogens are identified and antimicrobial therapy is adjusted according to the results obtained. Matching a DKD disease progression model to a drug mechanism of action model was used in a study by Pena et al. 45 A panel of serum metabolites being linked to molecular processes of inflammation and stress response, as well as downstream consequences of fibrosis and extracellular matrix rearrangement, was able to predict albuminuria response to ARBs in both type 1 and type 2 DM. This observation supports the concept that improved molecular characterization of drug effect and disease pathophysiology can predict treatment response.

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[20] Multimarker Panels in Diabetic Kidney Disease: The Way to Improved Clinical Trial Design and Clinical Practice?

Notes