👪

Inheritance

1

X-linked inheritance HP:0001417

Borjeson-Forssman-Lehmann syndrome is an X-linked disorder caused by pathogenic PHF6 variants, with variable expression in affected males and females.

X-linked inheritance

Show evidence (1 reference)

DOI:10.1038/s41598-020-75999-2 SUPPORT In Vitro

"Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females."

This directly supports X-linked inheritance and PHF6 causality in BFLS.

⚙

Pathophysiology

4

PHF6-related transcriptional dysregulation

PHF6 is a transcriptional regulator. Loss of PHF6 function disrupts transcriptional programs required for normal brain development in BFLS.

PHF6 link

regulation of transcription by RNA polymerase II link ⚠ ABNORMAL

Downstream

Ephrin receptor dysregulation PHF6 dysfunction perturbs direct transcriptional targets involved in neural stem cell control.

Abnormal neuronal morphogenesis Disrupted transcription alters downstream neuronal growth and migration programs.

Show evidence (1 reference)

DOI:10.1038/s44319-024-00082-0 SUPPORT Model Organism

"The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS)."

This establishes PHF6-dependent transcriptional regulation as the initiating molecular mechanism perturbed in BFLS.

Ephrin receptor dysregulation

PHF6 normally promotes Ephrin receptor expression in the developing brain. This regulatory step is impaired in BFLS models.

Downstream

Impaired neural stem cell regulation Loss of PHF6-dependent Ephrin receptor expression perturbs embryonic neural stem cell behavior.

Show evidence (1 reference)

DOI:10.1038/s44319-024-00082-0 SUPPORT Model Organism

"We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6."

This directly supports Ephrin receptor dysregulation as an intermediate mechanism downstream of PHF6 loss.

Impaired neural stem cell regulation

BFLS model systems show abnormal embryonic neural stem cell behavior with dysregulated self-renewal and altered neural progenitor output.

neural stem cell link

stem cell population maintenance link ⚠ ABNORMAL neural precursor cell proliferation link ⚠ ABNORMAL

Downstream

Intellectual disability Early neural stem cell dysregulation contributes to later cognitive impairment.

Seizure Abnormal neural precursor regulation contributes to downstream cortical dysfunction and seizure susceptibility.

Show evidence (2 references)

DOI:10.1038/s44319-024-00082-0 SUPPORT Model Organism

"Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors."

This supports abnormal neural stem cell regulation downstream of PHF6 dysfunction.

DOI:10.1371/journal.pgen.1011428 PARTIAL Model Organism

"Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons."

This provides partially concordant support for abnormal neural precursor regulation while indicating a directionally different self-renewal phenotype across BFLS models.

Abnormal neuronal morphogenesis

PHF6 loss impairs neuron proliferation, neurite extension, and migration in neuron-like cells.

neuron link

neuron migration link ⚠ ABNORMAL axon development link ⚠ ABNORMAL

Downstream

Intellectual disability Impaired neuronal development contributes to the core cognitive phenotype.

Show evidence (1 reference)

DOI:10.1038/s41598-020-75999-2 SUPPORT In Vitro

"Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration."

This directly supports abnormal neuronal development downstream of PHF6 loss.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

7

Breast 1

Gynecomastia Gynecomastia (HP:0000771)

Show evidence (1 reference)

DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical

"Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity."

This directly supports gynecomastia as a recurrent BFLS phenotype.

Ear 1

Large ears Macrotia (HP:0000400)

Show evidence (1 reference)

DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical

"Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity."

This directly supports large ears as part of the classic BFLS phenotype.

Endocrine 1

Hypogonadism Hypogonadism (HP:0000135)

Show evidence (1 reference)

DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical

"Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity."

This directly supports hypogonadism as a recurrent BFLS phenotype.

Head and Neck 1

Abnormal facial shape Abnormal facial shape (HP:0001999)

Show evidence (1 reference)

DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical

"Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity."

This directly supports a characteristic abnormal facial shape in BFLS.

Nervous System 2

Intellectual disability Intellectual disability (HP:0001249)

Show evidence (1 reference)

DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical

"AbstractBörjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene."

This directly identifies intellectual disability as the defining neurologic feature of BFLS.

Seizure Seizure (HP:0001250)

Show evidence (1 reference)

DOI:10.1371/journal.pgen.1011428 SUPPORT Model Organism

"We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism."

This model-organism evidence supports seizure susceptibility as part of the BFLS phenotype spectrum.

Growth 1

Obesity Obesity (HP:0001513)

Show evidence (1 reference)

DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical

"Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity."

This directly supports obesity, specifically truncal obesity, as a recurrent BFLS phenotype.

🧬

Genetic Associations

1

PHF6 (Causal variant)

Show evidence (3 references)

DOI:10.1038/s41598-020-75999-2 SUPPORT In Vitro

"Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females."

This directly supports PHF6 as the causal gene for BFLS.

DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical

"Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications."

This supports the sex-specific PHF6 variant pattern noted in the genetic section.

CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z SUPPORT Other

ClinGen classifies the PHF6-Borjeson-Forssman-Lehmann syndrome gene-disease relationship as definitive with X-linked inheritance.

{ }

Source YAML

click to show

name: Borjeson-Forssman-Lehmann syndrome
creation_date: "2026-04-15T15:45:03Z"
updated_date: "2026-04-16T00:04:54Z"
description: >-
  Borjeson-Forssman-Lehmann syndrome is a rare PHF6-related X-linked
  neurodevelopmental disorder characterized by intellectual disability and a
  syndromic pattern that can include obesity, hypogonadism, gynecomastia, and
  distinctive craniofacial features. Available mechanistic evidence supports
  PHF6-dependent transcriptional dysregulation with downstream Ephrin receptor
  dysregulation, abnormal neural stem cell regulation, and abnormal neuronal
  development.
category: Mendelian
parents:
- hereditary disease
- syndromic intellectual disability
synonyms:
- BFLS
disease_term:
  preferred_term: Borjeson-Forssman-Lehmann syndrome
  term:
    id: MONDO:0010537
    label: Borjeson-Forssman-Lehmann syndrome
inheritance:
- name: X-linked inheritance
  description: >-
    Borjeson-Forssman-Lehmann syndrome is an X-linked disorder caused by
    pathogenic PHF6 variants, with variable expression in affected males and
    females.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: DOI:10.1038/s41598-020-75999-2
    reference_title: Loss of PHF6 leads to aberrant development of human neuron-like cells
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females.
    explanation: This directly supports X-linked inheritance and PHF6 causality in BFLS.
pathophysiology:
- name: PHF6-related transcriptional dysregulation
  description: >-
    PHF6 is a transcriptional regulator. Loss of PHF6 function disrupts
    transcriptional programs required for normal brain development in BFLS.
  genes:
  - preferred_term: PHF6
    term:
      id: hgnc:18145
      label: PHF6
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  evidence:
  - reference: DOI:10.1038/s44319-024-00082-0
    reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS).
    explanation: This establishes PHF6-dependent transcriptional regulation as the initiating molecular mechanism perturbed in BFLS.
  downstream:
  - target: Ephrin receptor dysregulation
    description: PHF6 dysfunction perturbs direct transcriptional targets involved in neural stem cell control.
  - target: Abnormal neuronal morphogenesis
    description: Disrupted transcription alters downstream neuronal growth and migration programs.
- name: Ephrin receptor dysregulation
  description: >-
    PHF6 normally promotes Ephrin receptor expression in the developing brain.
    This regulatory step is impaired in BFLS models.
  evidence:
  - reference: DOI:10.1038/s44319-024-00082-0
    reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6.
    explanation: This directly supports Ephrin receptor dysregulation as an intermediate mechanism downstream of PHF6 loss.
  downstream:
  - target: Impaired neural stem cell regulation
    description: Loss of PHF6-dependent Ephrin receptor expression perturbs embryonic neural stem cell behavior.
- name: Impaired neural stem cell regulation
  description: >-
    BFLS model systems show abnormal embryonic neural stem cell behavior with
    dysregulated self-renewal and altered neural progenitor output.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: stem cell population maintenance
    modifier: ABNORMAL
    term:
      id: GO:0019827
      label: stem cell population maintenance
  - preferred_term: neural precursor cell proliferation
    modifier: ABNORMAL
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
  evidence:
  - reference: DOI:10.1038/s44319-024-00082-0
    reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors.
    explanation: This supports abnormal neural stem cell regulation downstream of PHF6 dysfunction.
  - reference: DOI:10.1371/journal.pgen.1011428
    reference_title: Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons.
    explanation: This provides partially concordant support for abnormal neural precursor regulation while indicating a directionally different self-renewal phenotype across BFLS models.
  downstream:
  - target: Intellectual disability
    description: Early neural stem cell dysregulation contributes to later cognitive impairment.
  - target: Seizure
    description: Abnormal neural precursor regulation contributes to downstream cortical dysfunction and seizure susceptibility.
- name: Abnormal neuronal morphogenesis
  description: >-
    PHF6 loss impairs neuron proliferation, neurite extension, and migration in
    neuron-like cells.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron migration
    modifier: ABNORMAL
    term:
      id: GO:0001764
      label: neuron migration
  - preferred_term: axon development
    modifier: ABNORMAL
    term:
      id: GO:0061564
      label: axon development
  evidence:
  - reference: DOI:10.1038/s41598-020-75999-2
    reference_title: Loss of PHF6 leads to aberrant development of human neuron-like cells
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration.
    explanation: This directly supports abnormal neuronal development downstream of PHF6 loss.
  downstream:
  - target: Intellectual disability
    description: Impaired neuronal development contributes to the core cognitive phenotype.
phenotypes:
- name: Intellectual disability
  category: Neurologic
  diagnostic: true
  description: Intellectual disability is a defining core feature of BFLS.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AbstractBörjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene.
    explanation: This directly identifies intellectual disability as the defining neurologic feature of BFLS.
- name: Obesity
  category: Metabolic
  description: Truncal obesity is a classic syndromic feature in affected males with BFLS.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity.
    explanation: This directly supports obesity, specifically truncal obesity, as a recurrent BFLS phenotype.
- name: Hypogonadism
  category: Endocrine
  description: Hypogonadism is a classic syndromic feature in affected males with BFLS.
  phenotype_term:
    preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity.
    explanation: This directly supports hypogonadism as a recurrent BFLS phenotype.
- name: Large ears
  category: Morphological
  description: Large ears are part of the classic craniofacial phenotype in affected males with BFLS.
  phenotype_term:
    preferred_term: Large ears
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity.
    explanation: This directly supports large ears as part of the classic BFLS phenotype.
- name: Gynecomastia
  category: Endocrine
  description: Gynecomastia is a classic endocrine phenotype in affected males with BFLS.
  phenotype_term:
    preferred_term: Gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity.
    explanation: This directly supports gynecomastia as a recurrent BFLS phenotype.
- name: Abnormal facial shape
  category: Morphological
  description: Distinctive facial appearance is part of the classic BFLS phenotype.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity.
    explanation: This directly supports a characteristic abnormal facial shape in BFLS.
- name: Seizure
  category: Neurologic
  description: Seizures occur in BFLS model systems and support a seizure-prone neurologic phenotype.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: DOI:10.1371/journal.pgen.1011428
    reference_title: Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism.
    explanation: This model-organism evidence supports seizure susceptibility as part of the BFLS phenotype spectrum.
biochemical: []
genetic:
- name: PHF6
  association: Causal variant
  gene_term:
    preferred_term: PHF6
    term:
      id: hgnc:18145
      label: PHF6
  notes: >-
    BFLS is caused by pathogenic PHF6 variants with sex-dependent phenotypic
    expression. Affected males often have missense variants or small in-frame
    deletions while affected females tend to have truncating variants or large
    deletions/duplications.
  evidence:
  - reference: DOI:10.1038/s41598-020-75999-2
    reference_title: Loss of PHF6 leads to aberrant development of human neuron-like cells
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females.
    explanation: This directly supports PHF6 as the causal gene for BFLS.
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications.
    explanation: This supports the sex-specific PHF6 variant pattern noted in the genetic section.
  - reference: CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z
    reference_title: "PHF6 / Borjeson-Forssman-Lehmann syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PHF6 | HGNC:18145 | Borjeson-Forssman-Lehmann syndrome | MONDO:0010537 | XL | Definitive"
    explanation: ClinGen classifies the PHF6-Borjeson-Forssman-Lehmann syndrome gene-disease relationship as definitive with X-linked inheritance.
environmental: []
treatments: []
diagnosis:
- name: PHF6 molecular genetic testing
  description: Molecular confirmation of a pathogenic PHF6 variant establishes the diagnosis of BFLS.
  presence: Identification of a pathogenic PHF6 variant confirms the diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: PHF6
        term:
          id: hgnc:18145
          label: PHF6
  evidence:
  - reference: DOI:10.1038/s41598-020-75999-2
    reference_title: Loss of PHF6 leads to aberrant development of human neuron-like cells
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females.
    explanation: This supports PHF6 molecular testing as the core confirmatory diagnostic procedure.
differential_diagnoses: []
clinical_trials: []
datasets: []
notes: >-
  Asta deep research was completed for this disorder. Final curation prioritized
  disease-specific human and mechanistic PHF6 papers with abstract-level support.

📚

References & Deep Research

Deep Research

1

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Borjeson-Forssman-Lehmann syndrome. Core disease mechanisms, molecular and...

Asta Scientific Corpus Retrieval 20 citations 2026-04-15T11:45:31.142880

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Borjeson-Forssman-Lehmann syndrome. Core disease mechanisms, molecular and...

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

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

Authors: M. M. Wong, L. Watson, Esther B. E. Becker
Year: 2017
Venue: Journal of neurology & neuromedicine
URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
DOI: 10.29245/2572.942X/2017/7.1134
PMID: 28825058
PMCID: 5558869
Citations: 9
Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
Evidence snippets:
Snippet 1 (score: 0.411) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[2] Loss of PHF6 leads to aberrant development of human neuron-like cells

Authors: Anna Fliedner, A. Gregor, F. Ferrazzi, A. Ekici, H. Sticht et al.
Year: 2020
Venue: Scientific Reports
URL: https://www.semanticscholar.org/paper/f2f43b6e6d05720f643288cc9ed9ce2900597142
DOI: 10.1038/s41598-020-75999-2
PMID: 33149206
PMCID: 7642390
Citations: 10
Summary: It is demonstrated that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration and might therefore contribute to the neurodevelopmental and cognitive dysfunction in BFLS.
Evidence snippets:
Snippet 1 (score: 0.401) > Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females. To investigate the mechanisms behind overlapping but distinct clinical aspects between genders, we assessed the consequences of individual variants with structural modelling and molecular techniques. We found evidence that de novo variants occurring in females are more severe and result in loss of PHF6, while inherited variants identified in males might be hypomorph or have weaker effects on protein stability. This might contribute to the different phenotypes in male versus female individuals with BFLS. Furthermore, we used CRISPR/Cas9 to induce knockout of PHF6 in SK-N-BE (2) cells which were then differentiated to neuron-like cells in order to model nervous system related consequences of PHF6 loss. Transcriptome analysis revealed a broad deregulation of genes involved in chromatin and transcriptional regulation as well as in axon and neuron development. Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration. Impairment of these processes might therefore contribute to the neurodevelopmental and cognitive dysfunction in BFLS.

[3] 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: 0.400) > 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.

[4] 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: 0.397) > 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.

[5] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
Year: 2023
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
DOI: 10.3389/fphar.2023.1290253
PMID: 38026943
PMCID: 10662320
Citations: 3
Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
Evidence snippets:
Snippet 1 (score: 0.394) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[6] Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome

Authors: Helen M. McRae, Melody Pui-Yee Leong, Maria I. Bergamasco, A. Garnham, Yifang Hu et al.
Year: 2024
Venue: PLOS Genetics
URL: https://www.semanticscholar.org/paper/8d31365b1878a146f68e332161beb9033e27d35a
DOI: 10.1371/journal.pgen.1011428
PMID: 39405291
PMCID: 11478892
Citations: 1
Influential citations: 1
Summary: It is shown that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS, providing insight into the molecular effects of loss of PHF6 in the developing brain.
Evidence snippets:
Snippet 1 (score: 0.392) > Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS. We report the phenotypic, anatomical, cellular and molecular characterization of the brain in males and females in two mouse models of BFLS, namely loss of Phf6 in the germline and nervous system-specific deletion of Phf6. We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism. Histological and morphological analysis revealed a significant enlargement of the lateral ventricles in adult Phf6-deficient mice, while other brain structures and cortical lamination were normal. Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons. Phf6 deficient cortical neurons commenced spontaneous neuronal activity prematurely suggesting precocious neuronal maturation. We show that loss of PHF6 in the foetal cortex and isolated cortical neurons predominantly caused upregulation of genes, including Reln, Nr4a2, Slc12a5, Phip and ZIC family transcription factor genes, involved in neural development and function, providing insight into the molecular effects of loss of PHF6 in the developing brain.

[7] 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: 0.392) > 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].

[8] Therapies for Mitochondrial Disease: Past, Present, and Future

Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
Year: 2025
Venue: Journal of Inherited Metabolic Disease
URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
DOI: 10.1002/jimd.70065
PMID: 40714961
PMCID: 12301291
Citations: 3
Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
Evidence snippets:
Snippet 1 (score: 0.388) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[9] 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: 0.386) > 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.

[10] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
DOI: 10.3390/ijms22031161
PMID: 33503868
PMCID: 7865492
Citations: 16
Influential citations: 1
Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
Evidence snippets:
Snippet 1 (score: 0.385) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[11] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
Year: 2025
Venue: Pathophysiology
URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
DOI: 10.3390/pathophysiology32010009
PMID: 39982365
PMCID: 12077258
Citations: 25
Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
Evidence snippets:
Snippet 1 (score: 0.383) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[12] 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: 0.382) > 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.

[13] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
Year: 2016
Venue: Molecular Psychiatry
URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
DOI: 10.1038/mp.2016.89
PMID: 27240529
PMCID: 4995546
Citations: 77
Influential citations: 2
Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
Evidence snippets:
Snippet 1 (score: 0.378) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[14] 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: 0.377) > 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.

[15] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

Authors: Xiao-lei Wu, Zhang-zhong Yang, Jinjun Zou, Huile Gao, Zhenhua Shao et al.
Year: 2025
Venue: Signal Transduction and Targeted Therapy
URL: https://www.semanticscholar.org/paper/57c532f807605e5181ca30a675ad0d79e3625453
DOI: 10.1038/s41392-025-02179-x
PMID: 40328798
PMCID: 12056177
Citations: 33
Influential citations: 1
Summary: The role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases are discussed, and the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies for effective prevention and early intervention are illustrated.
Evidence snippets:
Snippet 1 (score: 0.376) > Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

[16] Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective

Authors: J. Gervasoni, A. Primiano, M. Cicchinelli, L. Santucci, Serenella Servidei et al.
Year: 2024
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/07c164ce4ffbef88bb87a0761bc653dfb74eeeb0
DOI: 10.3390/ijms25094855
PMID: 38732076
PMCID: 11084339
Citations: 4
Summary: Omics technologies such as proteomics and metabolomics considered in this review, can support unresolved mitochondrial questions, helping to improve outcomes for patients.
Evidence snippets:
Snippet 1 (score: 0.372) > Mitochondrial diseases represent a large collection of rare neurometabolic syndromes characterized by extremely difficult clinical management, both chronically and during acute events. This condition is due to a lack of complete understanding of the metabolic and molecular mechanisms involved in the pathogenesis, and also to the absence of reliable diagnostic and prognostic biomarkers that are able to identify the disease in its multiple clinical manifestations and monitor its progression. Although genetic testing provides secure diagnoses, heteroplasmy, and gaps in knowledge of pathological mechanisms limit genomics in offering a comprehensive spectrum of diseases and their variations in severity and progression. Additionally, the absence of validated biomarkers has made identifying new therapies a challenge [24,25]. > Several techniques have developed to interrogate this complex process in multiple dimensions (DNA, RNA, proteins, and metabolites), known as "omics". These disciplines allow to investigate the different classes of biological components (genes-genomic, proteinsproteomic, and metabolites-metabolomic) that determine the phenotype of an organism. Different analytical techniques (Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) are used to identify either the metabolite patterns that are significant for the determination of the metabolic phenotype of the system under investigation, or the proteins used to determine of the alteration in the proteomic asset that can be identified as a possible marker of disease. Metabolomics and proteomic studies can be conducted with targeted, semi-targeted, and untargeted analytical approaches. Analysis is usually performed on multiple biological fluids: urine, saliva, plasma or serum, cerebrospinal fluid, cell cultures, tissue extracts, or biopsies. Through metabolic analysis, we can measure the metabolic profile, obtaining a fingerprint determined by the perturbation that is characteristic of the pathogenetic process [26].

[17] The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

Authors: M. Beaudin, A. Matilla-Dueñas, B. Soong, J. Pedroso, O. Barsottini et al.
Year: 2019
Venue: Cerebellum (London, England)
URL: https://www.semanticscholar.org/paper/8be333265c4faffaeb605213aa48cb23b33981c1
DOI: 10.1007/s12311-019-01052-2
PMID: 31267374
PMCID: 6867988
Citations: 49
Summary: A consensus is built on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders.
Evidence snippets:
Snippet 1 (score: 0.372) > The importance of a proper recessive ataxia classification goes beyond the clinical diagnosis perspective. Autosomal recessive ataxias can be regrouped according to the deficient cellular and metabolic pathways involved, which provide a better understanding of cerebellar physiology and of its selective vulnerability to certain metabolic defects. This is also essential from a therapeutic perspective, as disorders that belong to the same metabolic pathway may to the same treatment options, indicating potential for drug repurposing. Figure 3 presents a pathophysiological classification of autosomal recessive ataxias. Certain genes are presented more than once since some proteins are involved in several metabolic pathways or may interfere with other cellular processes as they accumulate in neurons or glial cells. Table 3 presents a more detailed listing of the pathogenic pathways involved along with relevant references. Certain pathways are predominantly involved, notably mitochondrial dysfunction, which may result from abnormal mitochondrial DNA maintenance with progressive mutagenesis, defective mitochondrial protein synthesis and quality control, increased levels of reactive oxygen species and oxidative stress, deficient coenzyme Q10 metabolism, altered mitochondrial dynamics, defective mitochondrial chain assembly, or abnormal mitochondrial RNA maturation and processing (Table 3). Interestingly, many of the disorders caused by mitochondrial dysfunction also present with a mitochondrial clinical syndrome as shown in Fig. 1. Disorders of DNA repair mechanisms are also common, with double-strand break repair pathway or single-strand break repair complexes predominantly involved. Pathogenic mutations in these genes are also associated with a susceptibility to ionizing radiations and predisposition for cancers, but the neurological syndrome is characterized by cerebellar involvement and extrapyramidal movement disorders. It remains debated whether defective DNA repair is the main pathogenic mechanism causing the neurological phenotype [230], but the fact that several interacting genes in this pathway are involved in degenerative cerebellar ataxias suggests that the cerebellum has a peculiar susceptibility to DNA damage for which the underlying mechanism is not understood. Finally, altered synaptic morphology or synaptic dysfunction of Purkinje cells (PC) is frequently involved in recessive ataxias and is associated with aberrant Fig. 1 Clinical classification of autosomal recessive ataxias.

[18] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

Authors: K. Lourida, G. Louridas
Year: 2022
Venue: Cardiogenetics
URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
DOI: 10.3390/cardiogenetics12020015
Citations: 4
Influential citations: 1
Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
Evidence snippets:
Snippet 1 (score: 0.371) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[19] 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: 0.370) > 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.

[20] “Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

Authors: D. Rovina, Elisa Castiglioni, Francesco Niro, Sara Mallia, G. Pompilio et al.
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/9303acc2a5c14adba1c342a87f27f2ae2a57195d
DOI: 10.3390/ijms21196997
PMID: 32977524
PMCID: 7582534
Citations: 3
Summary: Cardiovascular cells derived from muscular dystrophy patients’ induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies.
Evidence snippets:
Snippet 1 (score: 0.370) > Since inception, iPSC technology has shown enormous potential to model disease, solving many challenges associated with traditional approaches such as animal and primary cell/tissue models. On the basis of their characteristics, patient-specific iPSCs can provide disease-related cells which may have been previously inaccessible, e.g., neurons and cardiomyocytes. Taking advantage of these intrinsic properties, iPSCs carrying patient-specific mutations can be used to model the molecular mechanisms underlying the disease pathophysiology and screen responses to various types of therapeutics. The phenotype ranges that can be investigated by iPSC models involve a broad range of molecular, metabolic, electrophysiological, and cellular analytic techniques. iPSC disease models have been widely applied to study monogenic disorders that are caused by a single gene mutation [130] and sporadic complex disorders involving multiple or unknown genes [131]. The use of iPSC-based models for the latter disease type is more problematic with respect to monogenic diseases, since the phenotype is often the result of multiple small-effect genetic variants in combination with environmental factors. However, this approach was used to model many different complex diseases including Alzheimer's disease, Parkinson's disease, schizophrenia, and cardiac arrhythmias [132][133][134][135]. Without knowing the detailed underlying genetics, differentiated patient-specific iPSCs could provide disease-relevant cells that carry all the genetic elements implicated in the development of the disease and can be useful to analyze the common mechanisms of disease development. Indeed, patient-specific iPSCs obtained from multiple affected individuals that show similar phenotypes could be comparatively investigated in order to find common altered mechanistic pathways or functional activities. > One of the major issues concerning disease modeling using iPSCs is the relative immaturity of the cells differentiated from iPSCs. On the basis of this observation, iPSC-based models are considered more suitable for disorders with an early onset rather than late onset, for which cellular aging could play a role in the disease phenotype. However, despite their fetal phenotype, iPSC-derived cells have highlighted different phenotypes, suggesting that the pathology starts before the appearance of clinical symptoms, potentially allowing the discovery of novel mechanisms involved in the development of pathology [52,136]. > Recently, in

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Borjeson-Forssman-Lehmann syndrome. Core disease mechanisms, molecular and...

Relevant Papers

[1] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

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[5] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

[6] Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome

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

[8] Therapies for Mitochondrial Disease: Past, Present, and Future

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

[10] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

[11] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

[12] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

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

[15] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

[16] Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective

[17] The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

[18] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

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

[20] “Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

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