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Classifications

Harrison's Part

IUIS Category

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Inheritance

1

Autosomal Recessive HP:0000007

The deficiency state requires homozygosity for MASP2 p.D120G. Heterozygotes have reduced serum MASP-2 but retain lectin-pathway function and are not described as a disease state.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31828694 SUPPORT Human Clinical

"In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G"

States that the deficiency state is the homozygous genotype, which is what the recessive mode of inheritance rests on.

PMID:19307021 SUPPORT Human Clinical

"Heterozygosity for this allele significantly influenced the protein concentration, but not the lectin pathway of complement activity"

Separates the heterozygous carrier state, which lowers protein level without abolishing function, from the homozygous deficiency.

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Discussions and Knowledge Gaps

2

Why does a complete, non-redundant block of the lectin pathway produce no consistent clinical phenotype, when comparably complete blocks of the classical and terminal pathways produce characteristic ones?

KNOWLEDGE GAP masp2_complete_lesion_without_penetrance

Attached to

pathophysiology#Reduced Lectin Pathway Opsonization of Microbial Surfaces phenotypes#Recurrent Bacterial Infection

The usual explanation offered for an unpenetrant lectin-pathway deficiency is redundancy among the recognition molecules: lose ficolin-3 and mannose-binding lectin still initiates. That explanation is unavailable here. MASP-2 is the only protease that cleaves C4, so D120G homozygotes have no lectin-pathway activity by any route, and they are still mostly healthy. The remaining candidates are redundancy of the whole pathway against the classical and alternative pathways, an effect too small for the cohorts assembled so far, or an effect confined to people with a second immune defect. The third is the one with a positive signal behind it: the febrile neutropenia association was found in children already neutropenic from chemotherapy. What would discriminate the three is a cohort of genotyped homozygotes followed prospectively, with any second immune defect recorded, rather than homozygotes recovered by chance from case-control studies - which is how almost every published individual was found.

Do rare heterozygous MASP2 loss-of-function alleles belong to the same disease concept as D120G homozygosity?

KNOWLEDGE GAP masp2_rare_variants_versus_d120g

Attached to

pathophysiology#Impaired Lectin Pathway Antiviral Activity phenotypes#Herpes Simplex Virus Encephalitis

The herpes simplex encephalitis report is titled as MASP-2 deficiency, but its two patients are heterozygous for rare alleles that reduce secretion or block autoactivation, not homozygous for D120G. Heterozygotes for D120G have reduced MASP-2 protein with preserved pathway function, so if the encephalitis association is real it is unlikely to act through the same complete-pathway-loss mechanism, and may reflect a dominant-negative effect or a quantitative threshold specific to antiviral defence. dismech curates both under this entry because MONDO carries one term, but the two arms are kept as separate nodes and the phenotype record states which genotype it came from. Resolving this needs the two adults' alleles tested for pathway function in heterozygous serum, and D120G homozygotes assessed for herpes simplex encephalitis risk - neither of which has been done.

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Pathophysiology

4

MASP2 p.D120G Loss of Binding to Lectin Pathway Recognition Molecules

MASP-2 circulates in complexes with the recognition molecules of the lectin pathway and is activated when one of them binds a microbial or altered-self surface. The p.D120G substitution falls in the region that mediates that association: recombinant D120G MASP-2 does not bind mannose-binding lectin, so the enzyme is never recruited to a recognised surface. The variant is found in Europeans and in Inuit from West Greenland and not in the other populations surveyed.

Genetic context MASP2 hgnc:6902 functional_impact_category: LOSS_OF_FUNCTION

MASP-2 serine protease activity on recognised surfaces GO:0004252 ↓ DECREASED

Downstream

Failure of Lectin Pathway C4 Cleavage An enzyme that cannot be recruited to a recognised surface cannot cleave the substrate waiting there, so the binding defect is the whole of the functional defect.

Show evidence (2 references)

PMID:19234189 SUPPORT In Vitro

"We found that D120G and CHNHdup could not associate with MBL, whereas R99Q, P126L, H155R, V377A, R439H, and wild-type MASP-2 bound equally well to MBL."

The direct demonstration, in recombinant protein, that D120G abolishes the interaction with the recognition molecule. This is what LOSS_OF_FUNCTION rests on, and it distinguishes D120G from the several MASP2 polymorphisms that bind normally.

PMID:17252003 SUPPORT Human Clinical

"p.D120G was found only in Caucasians and Inuits from West-Greenland."

Establishes the population distribution of the causal allele, which is why the prevalence record below is restricted to Europeans.

Failure of Lectin Pathway C4 Cleavage

C4 is cleaved by MASP-2 alone among the MASPs, so loss of MASP-2 function removes the lectin pathway's route to the C3 convertase C4b2a and abolishes lectin-pathway activity outright. This is a stronger molecular lesion than a recognition-molecule deficiency such as ficolin-3 deficiency, where the remaining recognition molecules still reach the same enzyme. The classical and alternative pathways are unaffected.

complement activation, lectin pathway GO:0001867 ↓ DECREASED

Downstream

Reduced Lectin Pathway Opsonization of Microbial Surfaces C4b and the C3 convertase it forms are what deposit opsonins on a recognised surface, so a pathway that cannot cleave C4 deposits none by this route.

Impaired Lectin Pathway Antiviral Activity Proposed rather than established. The herpes simplex encephalitis report that motivates this node measured reduced antiviral activity for a rare MASP2 variant, not for D120G, so the edge is drawn from a different genetic lesion in the same gene, and how lectin-pathway activity restrains the virus is not established.

Show evidence (2 references)

PMID:31828694 SUPPORT BACKGROUND Human Clinical

"is an indispensable enzyme for the activation of the lectin pathway of complement"

States that the enzyme is non-redundant within the pathway, which is why the block is complete. The sentence is the paper's framing of MASP-2 biology rather than its own measurement.

PMID:15654829 SUPPORT Human Clinical

"As expected, MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele."

Confirms in patient serum, rather than in recombinant protein, that carrying a mutant MASP2 allele reduces measured lectin-pathway function.

Reduced Lectin Pathway Opsonization of Microbial Surfaces

With no lectin-pathway C4 cleavage, complement opsonins are not deposited by this route, and complement-receptor-mediated uptake of the organism by neutrophils and macrophages is correspondingly reduced. This is the mechanism the classification of MASP-2 deficiency as a primary immunodeficiency assumes. Whether it produces measurable susceptibility in people is the entry's central open question: the classical and alternative pathways still opsonise, and the evidence below runs both ways.

Neutrophil CL:0000775 Macrophage CL:0000235

opsonization GO:0008228 ↓ DECREASED phagocytosis GO:0006909 ↓ DECREASED

Downstream

Recurrent Bacterial Infection The proposed route from the molecular lesion to the clinical phenotype that the primary-immunodeficiency classification asserts. The edge is contested, not established; see the attached discussion and the REFUTE items on this node.

Autoimmunity Impaired complement-dependent handling of microbial and altered-self surfaces is the route by which early complement deficiencies are held to cause autoimmunity, and it is the basis of the autoimmunity half of the standing classification. No study of MASP-2-deficient individuals has demonstrated it.

Show evidence (4 references)

PMID:31828694 SUPPORT INDIRECT BACKGROUND Human Clinical

"Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity."

Records the standing classification that this node represents. The sentence reports how the deficiency is classified, not a measurement the paper made, and the same paper's own conclusion is curated as the REFUTE item below.

PMID:17984804 SUPPORT INDIRECT Human Clinical

"In this study, MASP-2 deficiency was associated with an increased risk of FN in children treated with chemotherapy for cancer."

The clearest positive clinical signal in the literature, and the support is indirect in two ways: deficiency here is a low serum MASP-2 concentration rather than a genotype, and the children were neutropenic from chemotherapy, so the finding bears on MASP-2 as a contributory factor under a second immune defect rather than on the deficiency alone.

PMID:31828694 REFUTE Human Clinical

"Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases."

The conclusion of the largest targeted study of the question, contradicting the claim that this node produces clinical susceptibility. Curated as REFUTE rather than omitted, because the disagreement is the state of the evidence.

+ 1 more reference

Impaired Lectin Pathway Antiviral Activity

Two adults with herpes simplex encephalitis carried rare heterozygous MASP2 missense variants, G634R and R203W, which reduce or abolish secretion of the protein and, for G634R, prevent autoactivation of the zymogen and reduce antiviral activity in vivo. This node is a different genetic architecture from the rest of the entry - rare heterozygous alleles in adults, not D120G homozygosity - and the association rests on two cases, so the node records a proposed antiviral role for the pathway rather than an established mechanism of MASP-2 deficiency.

Downstream

Herpes Simplex Virus Encephalitis Proposed on the strength of two adult cases with functionally defective rare MASP2 alleles and a mouse model lacking the associated recognition molecule.

Show evidence (2 references)

PMID:31869396 SUPPORT INDIRECT Human Clinical

"Altogether, these data suggest that MASP-2 deficiency can increase susceptibility to adult HSE."

The authors' own conclusion, which they state as a suggestion. Graded INDIRECT because the inference runs from two cases plus in vitro and mouse work to a susceptibility claim about the human deficiency state.

PMID:31869396 SUPPORT In Vitro

"a lost capability to cleave MASP-2 precursor into its active form"

The functional defect measured for the G634R allele, establishing that these are loss-of-function variants rather than incidental rare ones.

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Pathograph

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

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Phenotypes

3

Recurrent Bacterial Infection Immunological HP:0002718

Show evidence (4 references)

PMID:31828694 SUPPORT BACKGROUND Human Clinical

"Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity."

The standing classification that attributes pyogenic infection to this deficiency, quoted from the reviewing paper's framing of the field rather than from its own result.

PMID:31828694 REFUTE Human Clinical

"a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls"

Eleven affected individuals with no shared phenotype against nine healthy homozygotes is not the distribution a penetrant infection phenotype produces, which is why no frequency band is tagged on this record.

PMID:19307021 REFUTE Human Clinical

"That group had a shorter mean gestational age and a higher incidence of premature and low birthweight babies, but not of perinatal infections when compared with the others."

In 1788 neonates, biochemically MASP-2-deficient babies had no excess of perinatal infection. The deficiency here is defined by serum concentration, not genotype, so it bears on low MASP-2 generally rather than on the homozygous state specifically.

+ 1 more reference

Autoimmunity Immunological HP:0002960

Show evidence (2 references)

PMID:31828694 SUPPORT BACKGROUND Human Clinical

"inflammatory lung disease, and autoimmunity"

The autoimmunity half of the classification this record represents, quoted from the reviewing paper's framing rather than from its own result.

PMID:31828694 REFUTE Human Clinical

"individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases"

The study's own conclusion on the autoimmune half of the classification, reached after genotyping a lupus cohort and reviewing every published homozygote.

Herpes Simplex Virus Encephalitis Neurological HP:0012302

Show evidence (1 reference)

PMID:31869396 SUPPORT INDIRECT Human Clinical

"Altogether, these data suggest that MASP-2 deficiency can increase susceptibility to adult HSE."

The authors state the association as a suggestion drawn from two cases plus supporting functional and mouse data, which is why the support is graded indirect and no frequency is tagged.

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Genetic Associations

1

MASP2

Gene: MASP2 hgnc:6902 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:31828694 SUPPORT Human Clinical

"In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G"

Names the gene and the allele whose homozygosity defines the deficiency.

PMID:19234189 SUPPORT In Vitro

"In contrast, the R439H variant was deficient in this process despite its normal binding to MBL."

Supports the notes' claim that MASP2 carries several functionally distinct alleles, of which D120G is one, with different molecular consequences.

PMID:36574978 SUPPORT Human Clinical

"The prevalence of the rs72550870*G allele in the MASP2 gene associated with low serum protease activity was found to be increased in Russians compared with Nenets and Dolgan-Nganasans"

The population-distribution observation behind the selection hypothesis recorded in the notes.

Variants (1)

p.D120G Pathogenic

MASP2 c.359A>G, rs72550870. Abolishes association with mannose-binding lectin and so prevents lectin-pathway C4 cleavage; homozygosity is the deficiency state.

Show evidence (1 reference)

PMID:19234189 SUPPORT In Vitro

"We found that D120G and CHNHdup could not associate with MBL"

The functional consequence on which the pathogenic classification of this allele rests. The clinical consequence of carrying two copies is what this entry records as unsettled; the molecular consequence is not in dispute.

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Biochemical Markers

2

Serum MASP-2 concentration (DECREASED)

Show evidence (2 references)

PMID:19307021 SUPPORT Human Clinical

"Neonates with MASP-2 concentrations below 42 ng/ml were deemed to be MASP-2 deficient."

One of the two operational definitions in use, and the one applied in the largest cohort.

PMID:17252003 SUPPORT Human Clinical

"The MASP-2 levels were lowest in Africans from Zambia"

Supports the caveat that normal ranges differ by population, so a single numeric threshold does not transfer between cohorts.

Lectin pathway functional activity (DECREASED)

Show evidence (2 references)

PMID:19307021 SUPPORT Human Clinical

"Heterozygosity for this allele significantly influenced the protein concentration, but not the lectin pathway of complement activity"

Establishes that concentration and function come apart in heterozygotes, which is why both measurements are curated.

PMID:15654829 SUPPORT Human Clinical

"MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele"

Measured reduction of pathway function in serum from carriers of a mutant MASP2 allele.

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Prevalence

1

Europeans

Unknown 70.0–140.0 per 100,000

7 to 14 per 10,000 Europeans, which is the frequency of the p.D120G homozygous genotype rather than of a clinical phenotype. measure_type is UNKNOWN for that reason: most carriers of this genotype identified so far were found in control groups and were healthy, so reading the figure as a disease prevalence would assert the penetrance this entry records as unsettled. No prevalence_class is set. The range straddles a band boundary - 7 per 10,000 is below 1 in 1,000 and 14 per 10,000 is above it - so any single band would be a choice the source does not support. Only the range bounds (rate_low/rate_high) are recorded; no single rate_per_100000 is set, because the source gives a range and not a point estimate.

Show evidence (1 reference)

PMID:31828694 SUPPORT Human Clinical

"occurs in 7 to 14/10,000 individuals"

The source of the range this record normalizes to cases per 100,000.

{ }

Source YAML

click to show

name: Immunodeficiency Due To MASP-2 Deficiency
creation_date: "2026-10-15T02:18:25Z"
category: Mendelian
description: >-
  MASP-2 deficiency is an inherited defect of the lectin pathway of complement
  caused, in Europeans, by homozygosity for the MASP2 missense variant
  c.359A>G (p.D120G, rs72550870). MASP-2 is the protease that cleaves C4 after
  a lectin-pathway recognition molecule - mannose-binding lectin, a ficolin or
  a collectin - has bound its ligand, so it is the one component of the arm
  that none of the others can substitute for. The D120G substitution abolishes
  the interaction with mannose-binding lectin, so no C4 is cleaved and lectin
  pathway activity is lost completely rather than partially.

  Whether that loss is a disease is genuinely unsettled, and this entry curates
  the dispute rather than resolving it. The deficiency was reported in 2003 in
  an adult with autoimmune and inflammatory disease and recurrent pneumococcal
  infection, and has been listed since 2004 among the primary immunodeficiencies
  as a complement defect predisposing to pyogenic infection, inflammatory lung
  disease and autoimmunity. Against that, the largest targeted study found no
  homozygote among 1495 adults hospitalised with community-acquired pneumonia,
  103 children with invasive pneumococcal disease or 186 patients with systemic
  lupus erythematosus, while finding homozygotes among its healthy controls;
  its review of the literature counted eleven affected individuals with no
  shared phenotype against nine healthy homozygotes, nearly all of both groups
  found by chance in association studies. Its authors conclude that MASP-2 is
  largely redundant in human defence. Supporting negative results come from a
  neonatal cohort, a cystic fibrosis cohort and a MASP-2-deficient mouse line.
  The positive signals that survive are narrow: an excess of febrile
  neutropenia in children receiving chemotherapy, and two adults with herpes
  simplex encephalitis carrying rare MASP2 variants other than D120G.

  So the honest reading is of a complete, well-characterised molecular lesion
  with no established clinical penetrance. The entry records both readings, with
  the contradicting evidence curated as REFUTE items rather than omitted.
disease_term:
  preferred_term: immunodeficiency due to MASP-2 deficiency
  term:
    id: MONDO:0013423
    label: immunodeficiency due to MASP-2 deficiency
synonyms:
- MASP-2 deficiency
- MASP2 deficiency
- mannan-binding lectin-associated serine protease 2 deficiency
- mannose-binding lectin-associated serine protease-2 deficiency
parents:
- Complement Disorder
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      A primary complement deficiency listed among the inborn errors of immunity
      and discussed in terms of pyogenic infection and autoimmunity, placing it
      in Harrison's immune/rheumatologic Part beside the sibling
      Ficolin_3_Deficiency and Complement_Component_2_Deficiency entries.
  iuis_category:
    classification_value: complement deficiency
    notes: >-
      IUIS Table 8 carries a MASP2 deficiency row. This is the lectin-pathway
      enzyme row, as distinct from the lectin-pathway recognition-molecule row
      that Ficolin_3_Deficiency carries.
inheritance:
- name: Autosomal Recessive
  description: >-
    The deficiency state requires homozygosity for MASP2 p.D120G. Heterozygotes
    have reduced serum MASP-2 but retain lectin-pathway function and are not
    described as a disease state.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G"
    explanation: >-
      States that the deficiency state is the homozygous genotype, which is what
      the recessive mode of inheritance rests on.
  - reference: PMID:19307021
    reference_title: "Mannan-binding lectin-associated serine protease-2 (MASP-2) in a large cohort of neonates and its clinical associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for this allele significantly influenced the protein concentration, but not the lectin pathway of complement activity"
    explanation: >-
      Separates the heterozygous carrier state, which lowers protein level
      without abolishing function, from the homozygous deficiency.
pathophysiology:
- name: MASP2 p.D120G Loss of Binding to Lectin Pathway Recognition Molecules
  biological_scale: MOLECULAR
  description: >-
    MASP-2 circulates in complexes with the recognition molecules of the lectin
    pathway and is activated when one of them binds a microbial or altered-self
    surface. The p.D120G substitution falls in the region that mediates that
    association: recombinant D120G MASP-2 does not bind mannose-binding lectin,
    so the enzyme is never recruited to a recognised surface. The variant is
    found in Europeans and in Inuit from West Greenland and not in the other
    populations surveyed.
  genetic_context:
    gene:
      preferred_term: MASP2
      term:
        id: hgnc:6902
        label: MASP2
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: MASP-2 serine protease activity on recognised surfaces
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:19234189
    reference_title: "Polymorphisms in mannan-binding lectin (MBL)-associated serine protease 2 affect stability, binding to MBL, and enzymatic activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that D120G and CHNHdup could not associate with MBL, whereas R99Q, P126L, H155R, V377A, R439H, and wild-type MASP-2 bound equally well to MBL."
    explanation: >-
      The direct demonstration, in recombinant protein, that D120G abolishes the
      interaction with the recognition molecule. This is what LOSS_OF_FUNCTION
      rests on, and it distinguishes D120G from the several MASP2 polymorphisms
      that bind normally.
  - reference: PMID:17252003
    reference_title: "Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "p.D120G was found only in Caucasians and Inuits from West-Greenland."
    explanation: >-
      Establishes the population distribution of the causal allele, which is why
      the prevalence record below is restricted to Europeans.
  downstream:
  - target: Failure of Lectin Pathway C4 Cleavage
    causal_link_type: DIRECT
    description: >-
      An enzyme that cannot be recruited to a recognised surface cannot cleave
      the substrate waiting there, so the binding defect is the whole of the
      functional defect.
    evidence:
    - reference: PMID:19234189
      reference_title: "Polymorphisms in mannan-binding lectin (MBL)-associated serine protease 2 affect stability, binding to MBL, and enzymatic activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "when D120G and CHNHdup were mixed with MBL, no activation of complement factor C4 was observed"
      explanation: >-
        Tests the two steps in the same experiment: the variants that fail to
        associate with MBL are the variants that produce no C4 activation.
- name: Failure of Lectin Pathway C4 Cleavage
  biological_scale: MOLECULAR
  description: >-
    C4 is cleaved by MASP-2 alone among the MASPs, so loss of MASP-2 function
    removes the lectin pathway's route to the C3 convertase C4b2a and abolishes
    lectin-pathway activity outright. This is a stronger molecular lesion than a
    recognition-molecule deficiency such as ficolin-3 deficiency, where the
    remaining recognition molecules still reach the same enzyme. The classical
    and alternative pathways are unaffected.
  biological_processes:
  - preferred_term: complement activation, lectin pathway
    term:
      id: GO:0001867
      label: complement activation, lectin pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "is an indispensable enzyme for the activation of the lectin pathway of complement"
    explanation: >-
      States that the enzyme is non-redundant within the pathway, which is why
      the block is complete. The sentence is the paper's framing of MASP-2
      biology rather than its own measurement.
  - reference: PMID:15654829
    reference_title: "Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As expected, MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele."
    explanation: >-
      Confirms in patient serum, rather than in recombinant protein, that
      carrying a mutant MASP2 allele reduces measured lectin-pathway function.
  downstream:
  - target: Reduced Lectin Pathway Opsonization of Microbial Surfaces
    causal_link_type: DIRECT
    description: >-
      C4b and the C3 convertase it forms are what deposit opsonins on a
      recognised surface, so a pathway that cannot cleave C4 deposits none by
      this route.
  - target: Impaired Lectin Pathway Antiviral Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed rather than established. The herpes simplex encephalitis report
      that motivates this node measured reduced antiviral activity for a rare
      MASP2 variant, not for D120G, so the edge is drawn from a different
      genetic lesion in the same gene, and how lectin-pathway activity restrains
      the virus is not established.
- name: Reduced Lectin Pathway Opsonization of Microbial Surfaces
  biological_scale: CELLULAR
  description: >-
    With no lectin-pathway C4 cleavage, complement opsonins are not deposited by
    this route, and complement-receptor-mediated uptake of the organism by
    neutrophils and macrophages is correspondingly reduced. This is the
    mechanism the classification of MASP-2 deficiency as a primary
    immunodeficiency assumes. Whether it produces measurable susceptibility in
    people is the entry's central open question: the classical and alternative
    pathways still opsonise, and the evidence below runs both ways.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: opsonization
    term:
      id: GO:0008228
      label: opsonization
    modifier: DECREASED
  - preferred_term: phagocytosis
    term:
      id: GO:0006909
      label: phagocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity."
    explanation: >-
      Records the standing classification that this node represents. The
      sentence reports how the deficiency is classified, not a measurement the
      paper made, and the same paper's own conclusion is curated as the REFUTE
      item below.
  - reference: PMID:17984804
    reference_title: "Deficiency of mannose-binding lectin-associated serine protease-2 associated with increased risk of fever and neutropenia in pediatric cancer patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "In this study, MASP-2 deficiency was associated with an increased risk of FN in children treated with chemotherapy for cancer."
    explanation: >-
      The clearest positive clinical signal in the literature, and the support
      is indirect in two ways: deficiency here is a low serum MASP-2
      concentration rather than a genotype, and the children were neutropenic
      from chemotherapy, so the finding bears on MASP-2 as a contributory factor
      under a second immune defect rather than on the deficiency alone.
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases."
    explanation: >-
      The conclusion of the largest targeted study of the question,
      contradicting the claim that this node produces clinical susceptibility.
      Curated as REFUTE rather than omitted, because the disagreement is the
      state of the evidence.
  - reference: PMID:25548381
    reference_title: "Deficiency in mannose-binding lectin-associated serine protease-2 does not increase susceptibility to Trypanosoma cruzi infection."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Total absence of lectin pathway functional activity did not confer higher susceptibility to T. cruzi infection, suggesting that it plays a minor role in the immune response against this parasite."
    explanation: >-
      A MASP-2-deficient mouse line with no lectin-pathway activity at all is
      not more susceptible to a pathogen the pathway recognises in vitro. One
      organism in one species, so it bounds rather than settles the claim.
  downstream:
  - target: Recurrent Bacterial Infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The proposed route from the molecular lesion to the clinical phenotype
      that the primary-immunodeficiency classification asserts. The edge is
      contested, not established; see the attached discussion and the REFUTE
      items on this node.
  - target: Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired complement-dependent handling of microbial and altered-self
      surfaces is the route by which early complement deficiencies are held to
      cause autoimmunity, and it is the basis of the autoimmunity half of the
      standing classification. No study of MASP-2-deficient individuals has
      demonstrated it.
- name: Impaired Lectin Pathway Antiviral Activity
  biological_scale: CELLULAR
  description: >-
    Two adults with herpes simplex encephalitis carried rare heterozygous MASP2
    missense variants, G634R and R203W, which reduce or abolish secretion of the
    protein and, for G634R, prevent autoactivation of the zymogen and reduce
    antiviral activity in vivo. This node is a different genetic architecture
    from the rest of the entry - rare heterozygous alleles in adults, not D120G
    homozygosity - and the association rests on two cases, so the node records a
    proposed antiviral role for the pathway rather than an established mechanism
    of MASP-2 deficiency.
  evidence:
  - reference: PMID:31869396
    reference_title: "Herpes simplex encephalitis in adult patients with MASP-2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Altogether, these data suggest that MASP-2 deficiency can increase susceptibility to adult HSE."
    explanation: >-
      The authors' own conclusion, which they state as a suggestion. Graded
      INDIRECT because the inference runs from two cases plus in vitro and mouse
      work to a susceptibility claim about the human deficiency state.
  - reference: PMID:31869396
    reference_title: "Herpes simplex encephalitis in adult patients with MASP-2 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a lost capability to cleave MASP-2 precursor into its active form"
    explanation: >-
      The functional defect measured for the G634R allele, establishing that
      these are loss-of-function variants rather than incidental rare ones.
  downstream:
  - target: Herpes Simplex Virus Encephalitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed on the strength of two adult cases with functionally defective
      rare MASP2 alleles and a mouse model lacking the associated recognition
      molecule.
phenotypes:
- category: Immunological
  name: Recurrent Bacterial Infection
  description: >-
    Recurrent pyogenic infection is the phenotype the primary-immunodeficiency
    classification of MASP-2 deficiency asserts, and the 2003 index patient
    presented with it. No frequency is tagged, and that is the point of this
    record: the eleven published homozygous patients have no shared
    presentation, nine published homozygotes are healthy, and a study powered
    to find them identified no homozygote among 1495 adults with
    community-acquired pneumonia or 103 children with invasive pneumococcal
    disease. Both readings are curated below.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Its deficiency is classified as a primary immunodeficiency associated to pyogenic bacterial infections, inflammatory lung disease, and autoimmunity."
    explanation: >-
      The standing classification that attributes pyogenic infection to this
      deficiency, quoted from the reviewing paper's framing of the field rather
      than from its own result.
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "a total of eleven patients with a highly heterogeneous range of disorders and nine healthy controls"
    explanation: >-
      Eleven affected individuals with no shared phenotype against nine healthy
      homozygotes is not the distribution a penetrant infection phenotype
      produces, which is why no frequency band is tagged on this record.
  - reference: PMID:19307021
    reference_title: "Mannan-binding lectin-associated serine protease-2 (MASP-2) in a large cohort of neonates and its clinical associations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "That group had a shorter mean gestational age and a higher incidence of premature and low birthweight babies, but not of perinatal infections when compared with the others."
    explanation: >-
      In 1788 neonates, biochemically MASP-2-deficient babies had no excess of
      perinatal infection. The deficiency here is defined by serum
      concentration, not genotype, so it bears on low MASP-2 generally rather
      than on the homozygous state specifically.
  - reference: PMID:15654829
    reference_title: "Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No correlation to reduced lung function or need for lung transplantation was seen, either for MBL deficiency, MASP-2 gene mutation or reduced MBL pathway function."
    explanation: >-
      In a disease defined by chronic airway infection, where an opsonisation
      defect would be expected to show, MASP2 genotype did not track outcome.
- category: Immunological
  name: Autoimmunity
  description: >-
    Autoimmune and inflammatory disease was present in the index patient and is
    half of the standing classification, but no study of MASP-2-deficient
    individuals has borne it out. The targeted study found no p.D120G homozygote
    among 186 patients with systemic lupus erythematosus. No frequency is
    tagged.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "inflammatory lung disease, and autoimmunity"
    explanation: >-
      The autoimmunity half of the classification this record represents, quoted
      from the reviewing paper's framing rather than from its own result.
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals with MASP-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases"
    explanation: >-
      The study's own conclusion on the autoimmune half of the classification,
      reached after genotyping a lupus cohort and reviewing every published
      homozygote.
- category: Neurological
  name: Herpes Simplex Virus Encephalitis
  description: >-
    Reported in two adults carrying rare heterozygous MASP2 loss-of-function
    variants, G634R and R203W, identified in a screen of 15 adults with herpes
    simplex encephalitis against 294 controls. This is not the D120G homozygous
    deficiency the rest of the entry describes, and two cases cannot establish a
    phenotype; the record exists so the observation is visible rather than
    asserted as characteristic.
  phenotype_term:
    preferred_term: HSV encephalitis
    term:
      id: HP:0012302
      label: HSV encephalitis
  evidence:
  - reference: PMID:31869396
    reference_title: "Herpes simplex encephalitis in adult patients with MASP-2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Altogether, these data suggest that MASP-2 deficiency can increase susceptibility to adult HSE."
    explanation: >-
      The authors state the association as a suggestion drawn from two cases
      plus supporting functional and mouse data, which is why the support is
      graded indirect and no frequency is tagged.
prevalence:
- population: Europeans
  measure_type: UNKNOWN
  rate_low: 70.0
  rate_high: 140.0
  notes: >-
    7 to 14 per 10,000 Europeans, which is the frequency of the p.D120G
    homozygous genotype rather than of a clinical phenotype. measure_type is
    UNKNOWN for that reason: most carriers of this genotype identified so far
    were found in control groups and were healthy, so reading the figure as a
    disease prevalence would assert the penetrance this entry records as
    unsettled.

    No prevalence_class is set. The range straddles a band boundary - 7 per
    10,000 is below 1 in 1,000 and 14 per 10,000 is above it - so any single
    band would be a choice the source does not support. Only the range bounds
    (rate_low/rate_high) are recorded; no single rate_per_100000 is set, because
    the source gives a range and not a point estimate.
  evidence:
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occurs in 7 to 14/10,000 individuals"
    explanation: >-
      The source of the range this record normalizes to cases per 100,000.
biochemical:
- name: Serum MASP-2 concentration
  presence: DECREASED
  notes: >-
    The screening abnormality. There is no single agreed cut-off: a neonatal
    cohort set deficiency at below 42 ng/ml in cord serum while a paediatric
    oncology study used below 200 ng/mL, and normal medians differ severalfold
    between populations. A low concentration is not the same claim as the
    homozygous genotype, and several of the clinical associations in this entry
    were made on concentration rather than on genotype.
  evidence:
  - reference: PMID:19307021
    reference_title: "Mannan-binding lectin-associated serine protease-2 (MASP-2) in a large cohort of neonates and its clinical associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonates with MASP-2 concentrations below 42 ng/ml were deemed to be MASP-2 deficient."
    explanation: >-
      One of the two operational definitions in use, and the one applied in the
      largest cohort.
  - reference: PMID:17252003
    reference_title: "Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The MASP-2 levels were lowest in Africans from Zambia"
    explanation: >-
      Supports the caveat that normal ranges differ by population, so a single
      numeric threshold does not transfer between cohorts.
- name: Lectin pathway functional activity
  presence: DECREASED
  notes: >-
    The functional counterpart of the concentration measurement, and the one
    that distinguishes a deficiency state from a merely low level: homozygotes
    have no lectin-pathway activity, whereas heterozygotes have reduced protein
    with preserved activity.

    The two cohorts cited below disagree on heterozygote function. The neonatal
    cohort (PMID:19307021) found heterozygosity lowered the protein but not
    pathway activity; the cystic fibrosis cohort (PMID:15654829) found pathway
    function reduced in carriers of a mutant MASP-2 allele, who in that series
    were mostly heterozygous. The disagreement is left standing rather than
    resolved, because the two measured different populations with different
    assays.
  evidence:
  - reference: PMID:19307021
    reference_title: "Mannan-binding lectin-associated serine protease-2 (MASP-2) in a large cohort of neonates and its clinical associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for this allele significantly influenced the protein concentration, but not the lectin pathway of complement activity"
    explanation: >-
      Establishes that concentration and function come apart in heterozygotes,
      which is why both measurements are curated.
  - reference: PMID:15654829
    reference_title: "Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele"
    explanation: >-
      Measured reduction of pathway function in serum from carriers of a mutant
      MASP2 allele.
genetic:
- name: MASP2
  gene_term:
    preferred_term: MASP2
    term:
      id: hgnc:6902
      label: MASP2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    p.D120G is the allele behind essentially every reported European case. Other
    MASP2 missense alleles lower the protein or its activity without abolishing
    pathway function - V377A lowers serum levels with normal enzyme activity,
    P126L gives serum that is non-functional in homozygotes (PMID:17252003)
    although recombinant P126L cleaves C4 with activity comparable to wild-type
    (PMID:19234189) - the two results are reported together rather than
    reconciled - R439H binds mannose-binding lectin but cannot autoactivate and
    is common in sub-Saharan Africa - so a MASP2 variant and MASP-2 deficiency
    are not interchangeable.

    The geographic distribution of the D120G allele has been read as selection
    for low lectin-pathway activity: a Siberian survey found it commoner in
    Russians than in the Nenets and Dolgan-Nganasan aboriginal populations. That
    is a hypothesis the authors advance, not a demonstrated history.

    No ClinGen gene-disease validity assertion is recorded here because none was
    found for this pair; gene_disease_validity is left absent rather than filled
    with a curator's own tier.
  evidence:
  - reference: PMID:31828694
    reference_title: "Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Europeans, MASP-2 deficiency, due to homozygosity for c.359A > G"
    explanation: >-
      Names the gene and the allele whose homozygosity defines the deficiency.
  - reference: PMID:19234189
    reference_title: "Polymorphisms in mannan-binding lectin (MBL)-associated serine protease 2 affect stability, binding to MBL, and enzymatic activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, the R439H variant was deficient in this process despite its normal binding to MBL."
    explanation: >-
      Supports the notes' claim that MASP2 carries several functionally distinct
      alleles, of which D120G is one, with different molecular consequences.
  - reference: PMID:36574978
    reference_title: "Ficolin-3 and MASP-2 gene variants in Siberian arctic populations: Summarized evidence of selective pressure for the high frequency of lectin complement pathway deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of the rs72550870*G allele in the MASP2 gene associated with low serum protease activity was found to be increased in Russians compared with Nenets and Dolgan-Nganasans"
    explanation: >-
      The population-distribution observation behind the selection hypothesis
      recorded in the notes.
  variants:
  - name: p.D120G
    description: >-
      MASP2 c.359A>G, rs72550870. Abolishes association with mannose-binding
      lectin and so prevents lectin-pathway C4 cleavage; homozygosity is the
      deficiency state.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:19234189
      reference_title: "Polymorphisms in mannan-binding lectin (MBL)-associated serine protease 2 affect stability, binding to MBL, and enzymatic activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that D120G and CHNHdup could not associate with MBL"
      explanation: >-
        The functional consequence on which the pathogenic classification of
        this allele rests. The clinical consequence of carrying two copies is
        what this entry records as unsettled; the molecular consequence is not
        in dispute.
discussions:
- discussion_id: masp2_complete_lesion_without_penetrance
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Reduced Lectin Pathway Opsonization of Microbial Surfaces
  - phenotypes#Recurrent Bacterial Infection
  prompt: >-
    Why does a complete, non-redundant block of the lectin pathway produce no
    consistent clinical phenotype, when comparably complete blocks of the
    classical and terminal pathways produce characteristic ones?
  rationale: >-
    The usual explanation offered for an unpenetrant lectin-pathway deficiency
    is redundancy among the recognition molecules: lose ficolin-3 and
    mannose-binding lectin still initiates. That explanation is unavailable
    here. MASP-2 is the only protease that cleaves C4, so D120G homozygotes have
    no lectin-pathway activity by any route, and they are still mostly healthy.
    The remaining candidates are redundancy of the whole pathway against the
    classical and alternative pathways, an effect too small for the cohorts
    assembled so far, or an effect confined to people with a second immune
    defect.

    The third is the one with a positive signal behind it: the febrile
    neutropenia association was found in children already neutropenic from
    chemotherapy. What would discriminate the three is a cohort of genotyped
    homozygotes followed prospectively, with any second immune defect recorded,
    rather than homozygotes recovered by chance from case-control studies -
    which is how almost every published individual was found.
- discussion_id: masp2_rare_variants_versus_d120g
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Impaired Lectin Pathway Antiviral Activity
  - phenotypes#Herpes Simplex Virus Encephalitis
  prompt: >-
    Do rare heterozygous MASP2 loss-of-function alleles belong to the same
    disease concept as D120G homozygosity?
  rationale: >-
    The herpes simplex encephalitis report is titled as MASP-2 deficiency, but
    its two patients are heterozygous for rare alleles that reduce secretion or
    block autoactivation, not homozygous for D120G. Heterozygotes for D120G have
    reduced MASP-2 protein with preserved pathway function, so if the
    encephalitis association is real it is unlikely to act through the same
    complete-pathway-loss mechanism, and may reflect a dominant-negative effect
    or a quantitative threshold specific to antiviral defence.

    dismech curates both under this entry because MONDO carries one term, but
    the two arms are kept as separate nodes and the phenotype record states
    which genotype it came from. Resolving this needs the two adults' alleles
    tested for pathway function in heterozygous serum, and D120G homozygotes
    assessed for herpes simplex encephalitis risk - neither of which has been
    done.
notes: >-
  The entry's literature was assembled directly from PubMed rather than from a
  narrative deep-research report: the configured Falcon/Edison provider failed
  authentication on two attempts. The committed Asta report
  (research/Immunodeficiency_Due_To_MASP-2_Deficiency-deep-research-asta.md) is
  retrieval-only and surfaced no MASP-2 source this entry does not already
  cite - its retrieval is dominated by unrelated immunodeficiency and
  proteomics papers, which its own 16-of-36 on-topic count reflects. Every
  claim here is cited from a reference fetched into references_cache.

  Four sources that bear directly on this disease carry no abstract in PubMed
  and so could not be quoted: the 2003 index case report PMID:12904520, the
  low-penetrance letter PMID:17137870, the Polish homozygote case report
  PMID:24332888 and the tuberculosis case series PMID:24658431. Their content
  reaches this entry only through PMID:31828694, which reviews all of them, and
  claims that exist only in those papers - the index patient's individual
  features, the single-case descriptions - are deliberately left uncurated
  rather than cited to a text that cannot be checked.

  The counts quoted in the description and the discussions - eleven affected
  homozygotes, nine healthy ones, the cohort sizes - come from PMID:31828694,
  whose abstract states the eleven-and-nine figure and the cohort sizes. The
  per-individual breakdown sits in that paper's tables rather than its abstract,
  so it is described here and not quoted as an evidence snippet.

  No GeneReviews chapter exists for this disease: `just check-genereviews`
  reports NO_CHAPTER against the entry's name, its synonyms and its MONDO term,
  against the committed Bookshelf index.

  No treatments are curated. Nothing in the literature reviewed describes a
  treatment of MASP-2 deficiency itself, and for a deficiency whose clinical
  consequence is unsettled, writing one in from general complement-deficiency
  practice would assert a disease needing treatment.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

The entry's literature was assembled directly from PubMed rather than from a narrative deep-research report: the configured Falcon/Edison provider failed authentication on two attempts. The committed Asta report (research/Immunodeficiency_Due_To_MASP-2_Deficiency-deep-research-asta.md) is retrieval-only and surfaced no MASP-2 source this entry does not already cite - its retrieval is dominated by unrelated immunodeficiency and proteomics papers, which its own 16-of-36 on-topic count reflects. Every claim here is cited from a reference fetched into references_cache. Four sources that bear directly on this disease carry no abstract in PubMed and so could not be quoted: the 2003 index case report PMID:12904520, the low-penetrance letter PMID:17137870, the Polish homozygote case report PMID:24332888 and the tuberculosis case series PMID:24658431. Their content reaches this entry only through PMID:31828694, which reviews all of them, and claims that exist only in those papers - the index patient's individual features, the single-case descriptions - are deliberately left uncurated rather than cited to a text that cannot be checked. The counts quoted in the description and the discussions - eleven affected homozygotes, nine healthy ones, the cohort sizes - come from PMID:31828694, whose abstract states the eleven-and-nine figure and the cohort sizes. The per-individual breakdown sits in that paper's tables rather than its abstract, so it is described here and not quoted as an evidence snippet. No GeneReviews chapter exists for this disease: `just check-genereviews` reports NO_CHAPTER against the entry's name, its synonyms and its MONDO term, against the committed Bookshelf index. No treatments are curated. Nothing in the literature reviewed describes a treatment of MASP-2 deficiency itself, and for a deficiency whose clinical consequence is unsettled, writing one in from general complement-deficiency practice would assert a disease needing treatment.

Create: Immunodeficiency_Due_To_MASP-2_Deficiency · 2026-10-15T02:37:13Z · View source

New Mendelian entry for MASP-2 deficiency (MONDO:0013423, MASP2 hgnc:6902), curated against claim issue #14249 and replacing stubs/Immunodeficiency_Due_To_MASP-2_Deficiency.yaml. Deep research was unavailable: 'just research-disorder falcon' failed twice with 'Edison authentication failed' (503), so the literature was assembled directly from PubMed via the PubMed MCP tools and E-utilities, and every reference was fetched with 'just fetch-reference'. Curated content: a four-node pathograph running from the p.D120G loss of binding to mannose-binding lectin, through failure of lectin-pathway C4 cleavage, to reduced opsonisation and (separately, and flagged as a different genetic architecture) impaired antiviral activity; three phenotypes, all causally connected; a European genotype-frequency prevalence record; two biochemical markers; one MASP2 genetic record with the p.D120G variant; and two KNOWLEDGE_GAP discussions. The central curation decision is that clinical penetrance is unsettled and the entry says so rather than taking a side. Four evidence items are REFUTE: the targeted study's own redundancy conclusion (PMID:31828694) against both the infection and the autoimmunity phenotype, the neonatal cohort finding no excess perinatal infection (PMID:19307021), the cystic fibrosis cohort finding no outcome effect of MASP2 genotype (PMID:15654829), and the MASP-2-deficient mouse line not more susceptible to T. cruzi (PMID:25548381). No frequency band is tagged on any phenotype, and the prevalence record uses measure_type UNKNOWN with no prevalence_class, because the figure is a genotype frequency and the 7-14/10,000 range straddles a band boundary. Four papers that bear directly on the disease (PMID:12904520 index case, PMID:17137870, PMID:24332888, PMID:24658431) have no abstract in PubMed, so nothing is cited to them; this is recorded in the entry notes and claims unique to them are left uncurated. 'just check-genereviews' reports NO_CHAPTER for both name and synonyms. No treatments are curated, for the reason given in notes. kb/groupings/Complement_Deficiency_IEIs.yaml gains a member row for this entry (the lectin-pathway enzyme row beside the ficolin-3 recognition-molecule row) plus one stale-sentence fix in its notes; the edit was deliberately kept to the MASP2 row because a sibling PR is adding a C3 row to the same file. Validation: just validate, validate-terms, count-verified-snippets (29/29), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-enum-values, check-block-scalar-comments, check-coarse-phenotypes, check-term-cache-integrity and validate-disorders all pass; just validate-grouping and just check-groupings pass on the grouping with the new member SATISFIED.

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Immunodeficiency Due To MASP-2 Deficiency. Core disease mechanisms, molecu...

Asta Scientific Corpus Retrieval 20 citations 2026-10-15T02:39:56.748422

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Immunodeficiency Due To MASP-2 Deficiency. Core disease mechanisms, molecu...

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

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Atypical Clinical Presentation of Hidradenitis Suppurativa in a Patient with Severe Mannose-Binding Lectin Deficiency

Authors: S. Bhargava, Nils Becker, G. Kroumpouzos
Year: 2020
Venue: Case Reports in Dermatology
URL: https://www.semanticscholar.org/paper/28d6407734de7341307c75587f73f37a0c29e6ea
DOI: 10.1159/000507539
PMID: 32508615
PMCID: 7250386
Citations: 4
Summary: A 32-year-old woman with a history of recurrent painful, deep-seated abscesses and pustular lesions presented with an exceptionally low serum MBL level, which may reflect an enhancement of proinflammatory mechanisms.
Evidence snippets:
Snippet 1 (score: 0.474) > Mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs) are an essential component of innate immune response [1]. MBL is a collagen containing C-type lectin protein which helps in the opsonization of pathogens along with the activation of complement and cytokine production that promote chemotaxis and recruitment of inflammatory cells in an antibody-independent fashion [1]. An MBL level of <0.05 μg/mL is considered severe MBL deficiency whereas a level of 0.05-1 μg/mL indicates partial MBL deficiency [2]. MBL deficiency is the most common immunodeficiency in the general population, affecting 5-7% of individuals, although higher figures in Caucasians have been reported [1]. Severe MBL deficiency may occur independently of various primary immunodeficiency disorders, and 10.9% of patients with recurrent infections had MBL deficiency without primary immunodeficiency disorders [3]. Deficiencies of the MBL-MASP pathway are associated with recurrent infections, especially secondary to Staphylococcus aureus or Pseudomonas aeruginosa, as well as autoimmune and inflammatory skin disease and vascular complications [1]. However, there are very few reports describing dermatological manifestations in patients with MBL deficiency [1]. The reported skin manifestations in patients with MBL deficiency are outlined in Table 1. > Hidradenitis suppurativa (HS) has been associated with a spectrum of conditions, most of which belong to the group of autoinflammatory disorders [4]. MBL deficiency is not a reported comorbidity among hidradenitis patients [4,5]. We report a case of an atypical clinical presentation of HS in a patient with severe MBL deficiency who presented with recurrent abscesses -predominantly sterile, sterile folliculitis, and lymphadenopathy. Our extensive literature search did not reveal similar cases. Possible pathogenetic mechanisms of this rare clinical presentation are discussed.

[2] Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway

Authors: M. Isabel García-Laorden, Elisa Hernández-Brito, C. Muñoz-Almagro, Svetlana Pavlovic-Nesic, Í. Rúa-Figueroa et al.
Year: 2019
Venue: Journal of Clinical Immunology
URL: https://www.semanticscholar.org/paper/152604c2f5de5634f79f021e92d10f6c3c57c44f
DOI: 10.1007/s10875-019-00714-4
PMID: 31828694
PMCID: 7223972
Citations: 24
Summary: Cumulative evidence suggests that MASP-2, and even other components of the LP, are largely redundant in human defenses and that individuals with MASp-2 deficiency do not seem to be particularly prone to infectious or autoimmune diseases.
Evidence snippets:
Snippet 1 (score: 0.464) > We have performed an extensive study aimed to analyze MASP-2 deficiency due to the p.D120G variant in a large group of patients with CAP, IPD, or SLE and a large group of controls (both children and adults). Besides our three previously reported healthy individuals with MASP-2 deficiency [7,9], we herein report another MASP2 p.D120G homozygous individual who does not present particularly severe or recurrent infections, nor inflammatory or autoimmune diseases, or any other relevant disorder. > The study of individuals with PID has proven to be an important source of information on the relevance of the affected molecules in humans in nature [23]. The first case of MASP-2 deficiency, described in 2003 by Stengaard-Pedersen et al [6], > suggested that this was a new monogenic defect underlying an autosomal recessive immunodeficiency, predisposing to severe infections and autoimmunity. It is worth noting that this individual also showed low levels of C1q (with presence of anti-C1q autoantibodies), C3, and C4 and severely impaired classical and alternative pathways activity. This patient was identified when sera from 125 patients with suspected PID were analyzed for MBL-dependent LP activity deficiency [6,22]. Ten additional p.D120G homozygous patients (three children and seven adults), with a heterogeneous range of diseases, have been identified by chance in subsequent association studies [11][12][13][14][15][16][17][18] (Table 3). However, nine healthy individuals (two children and seven adults) homozygous for p.D120G have also been found by chance in genetic association studies [7, 9, 13, 17, 19-21, and this study]. Taken together, these findings suggest that MASP-2 deficiency no longer fulfills the premise that to establish a causal relationship between a genotype and a clinical phenotype, the genotype must not occur in healthy individuals [24].

[3] Recombinant human complement component C2 produced in a human cell line restores the classical complement pathway activity in-vitro: an alternative treatment for C2 deficiency diseases

Authors: P. Martini, L. Cook, Scott Alderucci, Angela W. Norton, Dianna M. Lundberg et al.
Year: 2010
Venue: BMC Immunology
URL: https://www.semanticscholar.org/paper/c8843ac8b31e821fdaabdf0d2d8c1e96e480a8f7
DOI: 10.1186/1471-2172-11-43
PMID: 20727163
PMCID: 2931460
Citations: 11
Summary: It is suggested that recombinant human C2 can restore classical complement pathway activity and may serve as a potential therapeutic for recurring bacterial infections or SLE in C2-deficient patients.
Evidence snippets:
Snippet 1 (score: 0.448) > Our understanding of the role of complement in human disease is the result of numerous studies in recent years focused on complement's mechanism of action. This has resulted in achieving important information on the role of complement as a major mediator and effector mechanism in diseases of immune and non-immune pathogenesis. Complement is not only important for protection against microorganisms, but also contributes to the pathophysiology of a number of autoimmune diseases. > Progress regarding the biological role of complement has been made by studying disease associations in patients with inherited complement protein deficiencies [1]. Genetic deficiencies of complement components are a common denominator of immune and infectious diseases. Deficiencies of complement components of the classical activation pathway, C1, C2 and C4, all lead to increased susceptibility to bacterial infections [2] and increased risk of developing autoimmune disease, particularly systemic lupus erythematosus (SLE) [3]. The complement system consists of more than 30 soluble and membrane proteins and constitutes an important mediator of host defense against foreign pathogens. Complement component C2 functions as a key regulator in the early activation phase of the classical pathway and participates in the formation of the classical pathway C3 convertase C4b2a [4]. C2 is also a critical component of the lectin pathway. Specifically, when mannose-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP) molecules bind to relevant carbohydrate molecules, this leads to activation of MASP-2 which then may cleave both C2 and C4 thereby forming the same C3 convertase as in classical pathway activation [5]. Thus, C2 is an important component of both the classical and the lectin pathways of complement activation and is involved in first line defense against microbial infection that is essential for detection and clearance of the invading pathogens [6]. > Complement C2 deficiency is the most common genetically determined complete complement deficiency with a prevalence estimated to be approximately 1:20,000 in individuals of Caucasian ancestry [3], making it a clinically important immune deficiency [7].

[4] “Complimenting the Complement”: Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma

Authors: Astha Malik, Unmesha Thanekar, S. Amarachintha, Reena Mourya, Shreya Nalluri et al.
Year: 2021
Venue: Frontiers in Oncology
URL: https://www.semanticscholar.org/paper/a710848e89914fc5c90cd216f8b7c330e724b1f0
DOI: 10.3389/fonc.2020.627701
PMID: 33718121
PMCID: 7943925
Citations: 35
Summary: Derangement of specific complement proteins in HCC is reviewed in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis.
Evidence snippets:
Snippet 1 (score: 0.444) > The MBL-associated protease MASP-2 predominantly promotes activation of the lectin complement pathway. While MASP-2 and lectin pathway components are highly conserved in immune defenses, loss of MASP-2 regulates infectious or autoimmune diseases, immunodeficiency of which are significantly associated with pyogenic bacterial infections, inflammatory lung disease, and autoimmunity (253). In oncogenic environments, increased levels of serum MASP and related lectin pathway molecules have been found to be associated with poor overall survival, disease progression, recurrence, and worse disease prognosis in patients with colorectal (254)(255)(256), ovarian (257), and cervical (258) cancers. Similar increases in MASP-2 protein were also associated with advanced clinical stages and nodal metastasis in esophageal squamous cell carcinoma (259). In agreement with these findings, serum MASP-2 levels were higher in pediatric patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma, and CNS tumors (260). However, significant variations between pediatric and adult patients have been documented. In contrast to the severe disease pathogenesis defined by elevated levels of MASP-2, MASP-2 deficiency in leukemic children on chemotherapy was associated with increased risk of febrile neutropenia (FN), antimicrobial therapy, and prolonged duration of hospitalization (261). Similarly, higher serum levels of MASP-2 were associated with impaired event-free survival in pediatric patients with lymphoma (262). Schlapbach et al. further showed that MASP-2 deficient children had significantly increased risk of developing FN in children on chemotherapy (263). These studies show MASP-2 deficiency as a potential risk factor for infections. In the context of HCC, analysis of patient secretomes derived from cancer and adjacent normal tissues using integrative transcriptomics and proteomics identified chitinase-3-like protein 1 (CHI3L1) and MASP2 as biomarkers in HCC diagnosis. However, when diagnosed in combination, the detection for HCC was further enhanced (264).

[5] Genetic basis of primary immunodeficiencies. Combined immunodeficiencies (review)

Authors: Людмила Бєляєва, K. V. Vovk, L. L. Sherstiuk, O. Vlasenko
Year: 2025
Venue: Karazin Journal of Immunology
URL: https://www.semanticscholar.org/paper/a4a5ad2e1863ecd20dd1c7876a723f9f09e55759
DOI: 10.26565/3083-5615-2025-15-09
Citations: 1
Summary: The analysis of the genetic basis of combined immunodeficiencies has revealed significant heterogeneity, covering a wide range of mutations in genes encoding proteins critical for the development and functioning of T- and B-lymphocytes.
Evidence snippets:
Snippet 1 (score: 0.432) > Background. Primary immunodeficiencies are a large and heterogeneous group of hereditary disorders characterized by disorders in the development, functioning or regulation of the immune system. The etiology of the vast majority of primary immunodeficiencies is directly related to genetic defects that may have different types of inheritance. Thanks to significant advances in molecular genetics and genomics in recent decades, a growing number of genes (currently more than 450) have been identified and characterized, with mutations leading to the development of these diseases. Primary immunodeficiencies demonstrate significant clinical and genetic heterogeneity. > Purpose – to review the key genetic defects, their mechanisms of influence on the immune system and the relationship with clinical manifestations of primary immunodeficiencies. > Materials and methods. The selection of publications was performed using the PubMed, Clinical Key Elsevier and Google Scholar databases, which covered the results of original research and review papers. At the first stage, we searched the literature using the following > Keywords: > primary immunodeficiencies, genetic defects, monogenic diseases, genetic polymorphism, immune system, clinical manifestations, mechanisms of development, molecular diagnostics, gene therapy. At the second stage, abstracts of articles were studied and publications that did not meet the study criteria were excluded. At the third stage, the full texts of the selected articles were studied for compliance with the criteria for inclusion in the list of references and relevance. > Results. The review takes an in-depth look at the key genetic defects underlying primary immunodeficiencies (the review is also devoted to the genetic basis of combined immunodeficiencies). The analysis of the genetic basis of combined immunodeficiencies has revealed significant heterogeneity, covering a wide range of mutations in genes encoding proteins critical for the development and functioning of T- and B-lymphocytes. The presence of specific mutations correlates with specific clinical phenotypes and disease severity. The findings emphasize the crucial importance of a genetic diagnosis for patients. In particular, a genetic diagnosis allows for personalized approaches to the treatment algorithm. Further research on genetic markers of immunodeficiencies is essential for the development of new diagnostic tools and innovative treatments. > Conclusions. The review of the category of combined immunodeficiencies demonstrates significant

[6] [Primary immunodeficiency and autoimmune diseases].

Authors: G. Műzes, F. Sipos
Year: 2018
Venue: Orvosi hetilap
URL: https://www.semanticscholar.org/paper/14a8db6d56e353b48c82e510366b6fe608ff76bb
DOI: 10.1556/650.2018.31064
PMID: 29860882
Citations: 5
Summary: The case presented finally highlights that both the recognition of autoimmune diseases in association with Immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging.
Evidence snippets:
Snippet 1 (score: 0.427) > Primary immunodeficiencies consist of a group of genetically heterogeneous immune disorders affecting distinct elements of the innate and adaptive immune system. Patients with primary immunodeficiency are more prone to develop not only recurrent infections, but non-infectious complications, like inflammatory or granulomatous conditions, lymphoproliferative and solid malignancies, autoinflammatory disorders, and a broad spectrum of autoimmune diseases. The concomitant appearance of primary immunodeficiency and autoimmunity appears to be rather paradoxical, therefore making the diagnosis of immunodeficiency patients with autoimmune complications challenging. Mutations of one or more genes playing a fundamental role in immunoregulation and/or immune tolerance network are thought to be responsible for primary immunodeficiencies. The diverse immunological abnomalities along with the compensatory and excessive sustained inflammatory response result in tissue damage and finally in manifestation of organ-, cell-specific or systemic autoimmune diseases. Several forms of primary immunodeficiency disorders are characterized by a variety of specific autoimmune phenomena. This overview addresses the spectrum of autoimmune diseases associated with primary immunodeficiencies, and explores the molecular and cellular mechanisms underlying abnormalities of the immune system. The case presented finally highlights that both the recognition of autoimmune diseases in association with immunodeficiencies and the diagnosis of immunodefiency in those phenotypes with predominant autoimmunity could be challenging. Orv Hetil. 2018; 159(23): 908-918.

[7] Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG.

Authors: Diana Gallego, Mercedes Serrano, José Córdoba-Caballero, A. Gámez, P. Seoane et al.
Year: 2024
Venue: Biochimica et biophysica acta. Molecular basis of disease
URL: https://www.semanticscholar.org/paper/44e382bb254b9af80c7134f4cd9873132d01685e
DOI: 10.1016/j.bbadis.2024.167163
PMID: 38599261
Citations: 13
Summary: Results presented from transcriptomic data might serve as a platform for identifying therapeutic targets for PMM2-CDG, as well as for monitoring the effectiveness of therapeutic strategies, including pharmacological candidates and mannose-1-P, drug repurposing.
Evidence snippets:
Snippet 1 (score: 0.426) > PMM2-CDG (MIM # 212065), the most common congenital disorder of glycosylation, is caused by the deficiency of phosphomannomutase 2 (PMM2). It is a multisystemic disease of variable severity that particularly affects the nervous system; however, its molecular pathophysiology remains poorly understood. Currently, there is no effective treatment. We performed an RNA-seq based transcriptomic study using patient-derived fibroblasts to gain insight into the mechanisms underlying the clinical symptomatology and to identify druggable targets. Systems biology methods were used to identify cellular pathways potentially affected by PMM2 deficiency, including Senescence, Bone regulation, Cell adhesion and Extracellular Matrix (ECM) and Response to cytokines. Functional validation assays using patients' fibroblasts revealed defects related to cell proliferation, cell cycle, the composition of the ECM and cell migration, and showed a potential role of the inflammatory response in the pathophysiology of the disease. Furthermore, treatment with a previously described pharmacological chaperone reverted the differential expression of some of the dysregulated genes. The results presented from transcriptomic data might serve as a platform for identifying therapeutic targets for PMM2-CDG, as well as for monitoring the effectiveness of therapeutic strategies, including pharmacological candidates and mannose-1-P, drug repurposing.

[8] Immunodeficiency due to MASP-2 deficiency

Authors: Unknown authors
Year: 2020
Venue: Definitions
URL: https://www.semanticscholar.org/paper/4e663a3826a7a669fe729ba897553d5e35eae30b
DOI: 10.32388/q18p77
Summary: Immunodeficiency due to MASP-2 deficiency is a rare, genetic immunodeficient due to a complement cascade protein anomaly characterized by low serum levels of MASP2 and a variable susceptibility to bacterial infections, autoimmune diseases, and autoimmune diseases.
Evidence snippets:
Snippet 1 (score: 0.410) > Immunodeficiency due to MASP-2 deficiency is a rare, genetic immunodeficiency due to a complement cascade protein anomaly characterized by low serum levels of MASP-2 and a variable susceptibility to bacterial infections (e.g. pulmonary tuberculosis, pneumococcal pneumonia, skin abscesses and sepsis), and autoimmune diseases (e.g. inflammatory lung disease, cystic fibrosis, systemic lupus erythematosus). In many cases it remains asymptomatic.

[9] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

Authors: Lina Zhu, Yang Li, Yi-Yao Bao
Year: 2026
Venue: Current Issues in Molecular Biology
URL: https://www.semanticscholar.org/paper/a5e1ddccfa7d333834c4d32be123c71bfd573f83
DOI: 10.3390/cimb48040422
PMID: 42042082
PMCID: 13114623
Summary: A comprehensive framework to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome is provided.
Evidence snippets:
Snippet 1 (score: 0.410) > Molecular genetic research on Bartter syndrome has made remarkable strides, elucidating the principal BS genes SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 and their corresponding protein defects, thereby refining the molecular framework of disease classification while separating CaSR-associated Bartter-like disease from the core canonical BS spectrum. This progress has significantly deepened our understanding of the underlying pathophysiology and provided an essential framework for correlating genotypes with clinical phenotypes. However, the intricate relationship between genetic mutations and clinical manifestations remains complex and multifaceted, reflecting the profound heterogeneity of the syndrome. Addressing these diagnostic challenges and refining disease classification beyond traditional clinical criteria requires an integrative approach that seamlessly balances high-throughput sequencing technologies with rigorous functional studies. > The mechanisms by which these genetic mutations lead to protein dysfunction are diverse, encompassing critical defects in protein expression, impaired membrane localization, and direct functional impairments. Notably, aberrant protein folding, endoplasmic reticulum-associated degradation (ERAD), and splicing abnormalities have emerged as critical pathogenic pathways. These mechanistic insights not only enhance our fundamental understanding of the disease but also highlight highly promising therapeutic targets. While current treatments remain predominantly symptomatic, focusing primarily on managing electrolyte imbalances and associated complications, they inherently fail to address the underlying molecular defects driving the disease. > The precise identification of specific molecular defects opens innovative avenues for the development of targeted interventions aimed at correcting or compensating for specific protein abnormalities. For instance, molecular chaperones that assist in protein folding, agents that modulate aberrant splicing, and future gene-based strategies represent important experimental directions for mechanism-based therapy. Consequently, the future of Bartter syndrome management may increasingly move toward precision medicine tailored to the molecular pathology of individual patients. However, the transition from concept to clinical implementation will require substantial additional functional, translational, and trial-level evidence. Such mechanism-based strategies promise not only to alleviate clinical symptoms but to fundamentally modify disease progression, thereby drastically improving long-term prognosis and quality of life for patients.

[10] Untargeted metabolomics reveals distinct metabolic profiles in MUT-type methylmalonic acidemia

Authors: Shuruq Alsuhaymi, Reem H. Almalki, Maha Al Mogren, Ahamd Alodaib, Abdul-Hamid M. Emwas et al.
Year: 2026
Venue: Molecular and Cellular Pediatrics
URL: https://www.semanticscholar.org/paper/4c2d95accb3bba4a721856ad7fb86ead52eca639
DOI: 10.1186/s40348-026-00250-3
PMID: 42448961
PMCID: 13369111
Citations: 1
Summary: The findings identify candidate disease-associated metabolites and provide insight into the metabolic disturbances associated with MMA, and highlight the importance of untargeted metabolomics to identify candidate biomarkers that could potentially predict long-term prognosis or represent novel therapeutic targets.
Evidence snippets:
Snippet 1 (score: 0.408) > Moreover, MUT gene defects can affect mitochondrial function, reduce ATP generation, and increase oxidative stress. These mitochondrial dysfunctions contribute to long-term complications, including chronic kidney disease, neurodevelopmental delays, cardiomyopathy, pancreatitis, and bone marrow suppression [9][10][11]. > The MMA clinical manifestations, mainly in early infancy, range widely from moderate to severe and life-threatening, depending on the type and degree of enzyme deficiency. Common symptoms in affected infants include recurrent vomiting, dehydration, reduced muscle tone (hypotonia), excessive fatigue (lethargy), and poor growth or failure to thrive. Moreover, metabolic acidosis, marked by an excess of acid in the blood, is a defining feature of MMA and, if untreated, can cause serious health complications, including acute metabolic decompensations (AMD) that may lead to coma or death. The underlying pathophysiology of AMD in isolated MMA remains incompletely understood. However, recent studies of MMA patient metabolomes suggest that metabolic acidosis during AMD is driven by the accumulation of acidic intermediates of branched-chain amino acid (BCAA) metabolism rather than methylmalonic acid levels. These findings emphasize the complexity of MMA and the need for further study to elucidate its acute and chronic mechanisms [12][13][14][15]. > Diagnosing MMA can be challenging due to its nonspecific clinical presentation and biochemical overlap with other inborn errors of metabolism. Although newborn screening (NBS) using tandem mass spectrometry (MS/MS) enables early detection by measuring more than 40 metabolites in dried blood spots, including propionylcarnitine (C3), the C3/acetylcarnitine (C2) ratio, and methionine, metabolite-based screening may be less reliable in clinically unstable or stressed newborns [16].

[11] 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
Citations: 2
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: 0.402) > 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.

[12] The ties that bind: functional clusters in limb-girdle muscular dystrophy

Authors: E. Barton, Christina A. Pacak, Whitney L. Stoppel, P. Kang
Year: 2020
Venue: Skeletal Muscle
URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
DOI: 10.1186/s13395-020-00240-7
PMID: 32727611
PMCID: 7389686
Citations: 25
Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
Evidence snippets:
Snippet 1 (score: 0.402) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[13] The ties that bind: functional clusters in limb-girdle muscular dystrophy

Authors: E. Barton, Christina A. Pacak, Whitney L. Stoppel, Peter B. Kang
Year: 2020
Venue: Skeletal Muscle
URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
DOI: 10.1186/s13395-020-00240-7
Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
Evidence snippets:
Snippet 1 (score: 0.402) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[14] Epigenetic Priming in Immunodeficiencies

Authors: J. Martínez-Cano, Elena Campos-Sánchez, C. Cobaleda
Year: 2019
Venue: Frontiers in Cell and Developmental Biology
URL: https://www.semanticscholar.org/paper/c73678330a46f7d4174138d15480efda7b04034a
DOI: 10.3389/fcell.2019.00125
PMID: 31355198
PMCID: 6635466
Citations: 17
Summary: It is proposed that epigenetics forms a “third axis” (together with genetics and external agents) to be considered in the etiology of IDs, and linking PIDs and SIDs at the molecular level.
Evidence snippets:
Snippet 1 (score: 0.401) > Human immunodeficiencies (IDs) are a large and heterogeneous group of diseases whose common underlying feature is a malfunctioning of the immune system that leads to an increased susceptibility to infections, often associated with autoimmunity and an elevated risk of cancer. Consequently, IDs have a significant disease-associated morbidity and, in the most severe cases, mortality. Broadly speaking, today, IDs are clinically grouped into two large subtypes according to their etiology: primary immunodeficiencies (PIDs), which are caused by congenital conditions (Picard et al., 2018) (see below), and secondary (acquired) immunodeficiencies (SIDs), which are the result of exposure of the organism to exogenous factors (infections, radiation, chemicals, aging, poor nutrition, etc.) (Chinen and Shearer, 2010). Each group is in itself subdivided in many different subtypes with distinct causes and varied clinical manifestations, and classification of IDs can be performed on the basis of very different criteria (clinical, molecular, cellular types affected, etc.) (Sullivan and Stiehm, 2014). > Primary immunodeficiencies constitute a heterogeneous group of more than 350 different disorders. They can appear isolated, only affecting the immune function, but they also often appear in the context of more complex multiorganic syndromes with a plethora of other associated defects (syndromic IDs; Ming et al., 2003). Most PIDs are of genetic origin and, with more than 340 genes identified already, new PIDs are being described in a rapidly increasing number (Bousfiha et al., 2018). The majority of PIDs are caused by either spontaneous of hereditary mutations affecting proteins with essential functions in the development and/or function of the cells of the immune system. The molecular pathways altered by these mutations can be many (Bousfiha et al., 2018), and the mechanisms of action leading to the final appearance of the immunodeficient phenotype can be very varied; in fact, many of them have not been completely clarified yet.

[15] Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice

Authors: Jovanka R. King, L. Hammarström
Year: 2017
Venue: Journal of Clinical Immunology
URL: https://www.semanticscholar.org/paper/2949b77dc538fbb075c38806a348130404d41320
DOI: 10.1007/s10875-017-0455-x
PMID: 29116556
PMCID: 5742602
Citations: 124
Influential citations: 3
Summary: The early origins of newborn screening and the evolution of screening methodologies are reviewed, the potential future role of protein-based assays, targeted sequencing, and next generation sequencing technologies are considered, including whole genome sequencing (WGS).
Evidence snippets:
Snippet 1 (score: 0.399) > Primary immunodeficiency diseases (PID) are a heterogeneous group of inborn errors of immunity, which were first recognized in the 1950s with the description by Ogden Bruton (1908Bruton ( -2003) ) of a young boy with recurrent infections and agammaglobulinemia [15]. Since this time, the broad clinical spectrum of PID has been recognized, and well over 300 different genetic mutations resulting in PID have been described to date [16]. Patients with PID typically present with a predisposition to infection, and delayed diagnosis results in significant complications and associated increased morbidity and mortality. PID present with a spectrum of clinical phenotypes and are caused by different pathophysiological mechanisms. They may be broadly classified as follows: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated or syndromic features, predominant antibody deficiencies, immune dysregulatory diseases, congenital defects of phagocyte number or function, innate or intrinsic immune defects, autoinflammatory disorders, complement deficiencies, or PID phenocopies [16]. > Severe combined immunodeficiency (SCID) is one of the most severe forms of PID and is manifested by a lack of T cells. B and NK cells may be variably absent depending on the molecular defect. This condition is an immunological emergency and requires prompt diagnosis and management. SCID is uniformly fatal without treatment. This condition came to public attention in the 1970s, when David Vetter (1971)(1972)(1973)(1974)(1975)(1976)(1977)(1978)(1979)(1980)(1981)(1982)(1983)(1984), known as the Bbubble boy,^was diagnosed with SCID and immediately after birth, was placed in a protective sterile environment at the Houston Children's Hospital in Texas. Unfortunately, a matched donor for hematopoietic stem cell transplantation (HSCT) was not available, and David lived in the Bbubble^until his death at age 13 years from EBV-associated lymphoma (https://primaryimmune.org/).

[16] Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Authors: Idan Hekselman, A. Vital, Maya Ziv-Agam, Lior Kerber, Ido Yairi et al.
Year: 2022
Venue: eLife
URL: https://www.semanticscholar.org/paper/f18f2a3134f7a0461c46b4d3c0c8f4248cf1961b
DOI: 10.1101/2022.10.29.513906
PMID: 38197427
PMCID: 10830129
Citations: 1
Summary: A method that infers disease-affected cell types from the preferential expression of disease-associated genes in cell types (PrEDiCT) was developed and applied to single-cell expression data of six human tissues, to infer the cell types affected in 1,113 hereditary diseases.
Evidence snippets:
Snippet 1 (score: 0.397) > So far, we assumed that the genes underlying a disease work through a single cellular context. However, the same disease phenotype might arise from mechanisms with distinct cellular contexts. For example, the bone-marrow disease hyper-IgM immunodeficiency could arise from mutations in CD40 gene, affecting B cells, or mutations in CD40 ligand (CD40LG), affecting CD4 T cells (Yazdani et al., 2019). In such cases the PrEDiCT scheme might fail to infer the affected cell types. Indeed, only CD4 T cells were predicted as likely affected by hyper-IgM immunodeficiency (PrEDiCT = 1.6, FDR <0.048). We hypothesized that the cellular context of such 'multi-cellular diseases' could be revealed by separately applying the PrEDiCT scheme to subsets of disease genes with distinct functions. > We first focused on diseases that alter intercellular communication. We identified seven diseases in our dataset that were caused by mutations in genes encoding ligands and their receptors. Next, we applied PrEDiCT scheme separately to ligands and to receptors (Methods). As expected, hyper-IgM immunodeficiency was found to likely affect naïve B cells through CD40 (receptor; PrEDiCT = 2.9, FDR = 0.06), and CD4αβ T cells through CD40LG (ligand; PrEDiCT = 3.7, FDR <0.001; Figure 4A). Another example is autosomal recessive limb-girdle muscular dystrophy, which is caused by mutations in laminin-α2 (LAMA2) or its receptor α-dystroglycan (DAG1). By applying PrEDiCT scheme without subdividing the disease genes, we could not infer any likely affected cell type. Yet, by separately applying body anemias across mouse bone marrow cell types depicted as described in panel C. (E) PrEDiCT scores of mitochondrial complex deficiencies across mouse skeletal muscle cell types depicted as described in panel C. Mitochondrial complex deficiencies were likely associated with striated muscle cells, except for mitochondrial complex II deficiency whose PrEDiCT scores were highest yet insignificant in these cell types (FDR = 0.65).

[17] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, P. 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: 39
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: 0.395) > 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.

[18] Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency

Authors: A. Szczawińska-Popłonyk, Wiktoria Ciesielska, Marta Konarczak, Jakub Opanowski, Aleksandra Orska et al.
Year: 2024
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/3c224ef8c5dc743ab11626dd1064b356b0b9732b
DOI: 10.3390/ijms25189999
PMID: 39337487
PMCID: 11432681
Citations: 5
Summary: The aspects of genetics in CVID are reviewed, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology, and the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes are discussed.
Evidence snippets:
Snippet 1 (score: 0.394) > Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development.

[19] Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

Authors: G. del Favero, A. Bonifacio, T. Rowland, Shan-Shan Gao, Kunhua Song et al.
Year: 2020
Venue: Journal of Clinical Medicine
URL: https://www.semanticscholar.org/paper/98c99997015d4b753548454628875ce01936b442
DOI: 10.3390/jcm9082457
PMID: 32751926
PMCID: 7465084
Citations: 21
Influential citations: 1
Summary: Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
Evidence snippets:
Snippet 1 (score: 0.394) > Because Danon disease is very rare, with <100 clinical reports and <200 families reported in the literature [12], there is poor availability of material for diagnosis and characterization [13]. Hence, research toward the creation of reliable models, such as animal models [14] or iPSC-CMs, enabling the study of this complex pathology even in a limited manner are essential and constantly evolving. > To determine the molecular and cellular mechanisms by which LAMP-2 deficiency results in metabolic changes, here we combined Raman spectroscopy, transcriptomics, and metabolomics approaches on cardiac tissue and cellular models derived from Danon patients. Analyses were performed on cardiac tissue biopsies from Danon patients, as well as from patient-derived hiPSC-CMs. Even with limited patient cardiac tissue, we were able to identify pathways that were similarly impacted in our cellular models, supportive of these pathways being significantly affected in Danon disease. LAMP-2 deficiency appeared to promote specific metabolic switch in cardiomyocytes, possibly adaptive, given that cardiomyocytes have a high metabolic need. The pathway analyses suggest that LAMP-2 deficiency favors glycolysis to oxidative phosphorylation (OXPHOS) and promotes alternative metabolic pathways, such as with the mobilization of tryptophan. This contributes to preserving high nicotinamide adenine dinucleotide (NAD + ) levels despite mitochondrial aging. Similarly, fibroblasts respond to LAMP-2 deficiency with a stress-associated phenotype pointing toward fibrosis progression. This was accompanied by impairment of biomechanical properties, which retraces the clinical phenotype of Danon disease.

[20] NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency

Authors: D. Lenz, J. Pahl, F. Hauck, S. Alameer, M. Balasubramanian et al.
Year: 2021
Venue: Journal of Clinical Immunology
URL: https://www.semanticscholar.org/paper/1c81ce9e4c9b532742111856c03b9dfacd0c84f5
DOI: 10.1007/s10875-021-01110-7
PMID: 34386911
PMCID: 8604887
Citations: 20
Summary: It is demonstrated that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.
Evidence snippets:
Snippet 1 (score: 0.392) > We show that NK cell activation and degranulation were improved by pre-activation of NK cells with IL-2 in vitro in patients from the "β-propeller" and "Sec39" subgroup, suggesting that IL-2 might enhance NBAS expression and/ or function or promote alternative molecular pathways mediating cytolytic vesicle release in those. Similarly, NK cell degranulation was shown to be improved after 48-72-h IL-2 stimulation in NK cells of FHL4 patients due to variants in STX11 and FHL5 due to variants in STXBP2, with both genes coding for SNARE proteins [29,38]. Hence, cytokine therapy with clinically approved IL-2 or IL-15 formulations [36,39,40] might support NK cell function in NBAS-deficient patients. Clearly, future indepth mechanistic studies are warranted to better understand the complex pathophysiology of NBAS deficiency. > In conclusion, NBAS variants cause a multisystem disease including an immunodeficiency phenotype marked by low NK cell numbers and NK cell dysfunction as well as reduction of naïve B cells and serum immunoglobulin levels. Patients with pathogenic NBAS variants should be investigated accordingly.

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Unresolved (possible confabulation)	0
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References weighed for topical relevance	36
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Immunodeficiency Due To MASP-2 Deficiency

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Immunodeficiency Due To MASP-2 Deficiency. Core disease mechanisms, molecu...

Relevant Papers

[1] Atypical Clinical Presentation of Hidradenitis Suppurativa in a Patient with Severe Mannose-Binding Lectin Deficiency

[2] Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway

[3] Recombinant human complement component C2 produced in a human cell line restores the classical complement pathway activity in-vitro: an alternative treatment for C2 deficiency diseases

[4] “Complimenting the Complement”: Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma

[5] Genetic basis of primary immunodeficiencies. Combined immunodeficiencies (review)

[6] [Primary immunodeficiency and autoimmune diseases].

[7] Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG.

[8] Immunodeficiency due to MASP-2 deficiency

[9] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

[10] Untargeted metabolomics reveals distinct metabolic profiles in MUT-type methylmalonic acidemia

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

[12] The ties that bind: functional clusters in limb-girdle muscular dystrophy

[13] The ties that bind: functional clusters in limb-girdle muscular dystrophy

[14] Epigenetic Priming in Immunodeficiencies

[15] Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice

[16] Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

[17] New therapeutic targets in rare genetic skeletal diseases

[18] Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency

[19] Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

[20] NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency

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