Renal hypomagnesemia 4 (HOMG4), also called isolated recessive renal hypomagnesemia, is an autosomal recessive renal magnesium-wasting disorder caused by a homozygous missense variant in EGF, the gene for pro-epidermal growth factor. The variant, p.Pro1070Leu, removes the second proline of a PXXP basolateral sorting motif in the cytoplasmic tail of pro-EGF, so the precursor is no longer delivered to the basolateral membrane of distal convoluted tubule (DCT) cells. Without basolateral EGF, the EGF receptor on DCT cells is not stimulated and the apical magnesium channel TRPM6 is not activated, so tubular magnesium reabsorption fails and magnesium is lost in the urine. Serum and urinary calcium remain normal. The disease is known from a single consanguineous Dutch family, in which two sisters had low serum magnesium with inappropriately high urinary magnesium, epileptic seizures from the first year of life, psychomotor delay in childhood and moderate intellectual disability as adults. The renal mechanism is supported by cell studies and by the hypomagnesemia seen with the EGFR antibody cetuximab. Why the sisters are intellectually disabled is not known, and the original clinicians judged the convulsions to be unrelated to hypomagnesemia.
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name: Renal Hypomagnesemia 4
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
description: >-
Renal hypomagnesemia 4 (HOMG4), also called isolated recessive renal
hypomagnesemia, is an autosomal recessive renal magnesium-wasting disorder
caused by a homozygous missense variant in EGF, the gene for pro-epidermal
growth factor. The variant, p.Pro1070Leu, removes the second proline of a
PXXP basolateral sorting motif in the cytoplasmic tail of pro-EGF, so the
precursor is no longer delivered to the basolateral membrane of distal
convoluted tubule (DCT) cells. Without basolateral EGF, the EGF receptor on
DCT cells is not stimulated and the apical magnesium channel TRPM6 is not
activated, so tubular magnesium reabsorption fails and magnesium is lost in
the urine. Serum and urinary calcium remain normal. The disease is known from
a single consanguineous Dutch family, in which two sisters had low serum
magnesium with inappropriately high urinary magnesium, epileptic seizures
from the first year of life, psychomotor delay in childhood and moderate
intellectual disability as adults. The renal mechanism is supported by cell
studies and by the hypomagnesemia seen with the EGFR antibody cetuximab. Why
the sisters are intellectually disabled is not known, and the original
clinicians judged the convulsions to be unrelated to hypomagnesemia.
notes: >-
The entry is anchored on MONDO:0012717 (OMIM 611718) and EGF (hgnc:3229).
All human data come from one family with two affected sisters, so no
frequency band is recorded and every phenotype should be read as a two-case
observation.
Seizures and intellectual disability are curated as phenotypes without an
incoming edge from the magnesium-wasting chain. The 1987 clinical report
states that the convulsions were unrelated to hypomagnesemia (PMID:3436090),
and the 2007 molecular report raises EGF's role in brain development as an
open question (PMID:17671655). Linking either phenotype to hypomagnesemia
would assert a mechanism neither source supports.
No treatment specific to this disease has been studied. Magnesium
replacement is the general management of renal magnesium wasting, but no
cited source reports it in these patients, so it is not curated as a
treatment.
No GeneReviews chapter covers this disease; just check-genereviews reports
NO_CHAPTER against the 2026-09-10 Bookshelf index.
No source was found for a magnesium phenotype in Egf-knockout mice.
Searches run on 2026-10-15: PubMed "(EGF OR epidermal growth factor) AND
(knockout OR null OR deficient) AND mice AND magnesium" (eight results, none
on an Egf-null mouse) and Europe PMC "\"Egf knockout mice\" AND magnesium"
(one unrelated result). The cached full texts of PMID:17671655,
PMID:17671646 and PMID:19073827 contain no knockout result.
disease_term:
preferred_term: renal hypomagnesemia 4
term:
id: MONDO:0012717
label: renal hypomagnesemia 4
synonyms:
- HOMG4
- hypomagnesemia 4, renal
- isolated recessive renal hypomagnesemia
- isolated autosomal recessive renal hypomagnesemia
- EGF-related primary hypomagnesemia
- EGF-related primary hypomagnesemia with intellectual disability
parents:
- Primary Hypomagnesemia
- Renal Tubulopathy
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Both affected sisters are homozygous for EGF p.Pro1070Leu. The parents, two
unaffected sisters and a paternal aunt are heterozygous and unaffected.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found that both parents and the 2 unaffected sisters (Figure 1A) of this Dutch family were heterozygous for the mutation."
explanation: >-
Unaffected heterozygous relatives and homozygous affected sisters
support recessive inheritance.
- reference: PMID:3436090
reference_title: "Isolated autosomal recessive renal magnesium loss in two sisters."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A familial autosomal recessive form of isolated renal magnesium loss is presented."
explanation: The original clinical description of the family.
prevalence:
- population: Worldwide reported literature
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Two affected sisters from one Dutch family are the only molecularly
confirmed cases.
evidence:
- reference: PMID:3436090
reference_title: "Isolated autosomal recessive renal magnesium loss in two sisters."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two children in this family suffered from convulsions unrelated to hypomagnesemia."
explanation: >-
Documents the two affected children of the only reported family.
pathophysiology:
- name: Homozygous EGF p.Pro1070Leu Variant
biological_scale: MOLECULAR
description: >-
The c.3209C>T variant replaces proline 1070, the second proline of the
1067PKNP1070 basolateral sorting motif in the cytoplasmic tail of pro-EGF,
with leucine.
genes:
- preferred_term: EGF
term:
id: hgnc:3229
label: EGF
molecular_functions:
- preferred_term: epidermal growth factor receptor binding
description: >-
Mutant EGF can still bind its receptor. The decrease is in binding at
the basolateral surface of DCT cells, because the precursor is not
delivered there.
term:
id: GO:0005154
label: epidermal growth factor receptor binding
modifier: DECREASED
genetic_context:
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected individuals both have a homozygous mutation C3209T in exon 22, resulting in the amino acid substitution P1070L."
explanation: Identifies the causal variant in both affected sisters.
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "P1070 is strongly conserved among different species and forms the second proline of a basolateral PXXP sorting motif."
explanation: Places the substituted residue in a basolateral sorting motif.
downstream:
- target: Impaired Basolateral Sorting of Pro-EGF
causal_link_type: DIRECT
description: >-
Loss of the sorting motif stops pro-EGF from reaching the basolateral
membrane of polarized epithelial cells; apical delivery is unaffected.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The mutation leads to impaired basolateral sorting of pro-EGF."
explanation: >-
States the direct consequence of the variant. The abstract sentence
summarizes the paper's polarized MDCK experiments, so it is graded
IN_VITRO rather than by the paper's clinical design.
- name: Impaired Basolateral Sorting of Pro-EGF
biological_scale: CELLULAR
description: >-
Polarized cells expressing mutant pro-EGF release EGF activity into the
apical medium as wild-type cells do, but not into the basolateral medium,
where the EGF receptor of DCT cells sits.
cell_types:
- preferred_term: kidney distal convoluted tubule epithelial cell
term:
id: CL:1000849
label: kidney distal convoluted tubule epithelial cell
biological_processes:
- preferred_term: protein localization to basolateral plasma membrane
term:
id: GO:1903361
label: protein localization to basolateral plasma membrane
modifier: DECREASED
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, stimulation of TRPM6 channel activity was only observed with basolaterally collected wild-type pro-EGF medium, not with the basolateral mutant pro-EGF media (Figure 3E)."
explanation: >-
In polarized MDCK cells, mutant pro-EGF fails to deliver active EGF to
the basolateral side.
downstream:
- target: Inadequate Renal EGFR Stimulation
causal_link_type: DIRECT
description: >-
Without basolateral EGF, the basolateral EGF receptor of DCT cells is
under-stimulated.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "As a consequence, the renal EGFR is inadequately stimulated, resulting in insufficient activation of the epithelial Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) and thereby Mg(2+) loss."
explanation: >-
States the link from missorted pro-EGF to EGFR under-stimulation. The
conclusion about the kidney is drawn from MDCK and HEK293 assays, so
it is IN_VITRO and indirect.
- name: Inadequate Renal EGFR Stimulation
biological_scale: CELLULAR
description: >-
EGF acts as a local magnesiotropic signal on EGFR at the basolateral
membrane of DCT cells. Blocking EGFR with cetuximab in cancer patients
lowers serum magnesium, which supports this step independently of the
family.
cell_types:
- preferred_term: kidney distal convoluted tubule epithelial cell
term:
id: CL:1000849
label: kidney distal convoluted tubule epithelial cell
genes:
- preferred_term: EGFR
term:
id: hgnc:3236
label: EGFR
molecular_functions:
- preferred_term: transmembrane receptor protein tyrosine kinase activity
term:
id: GO:0004714
label: transmembrane receptor protein tyrosine kinase activity
modifier: DECREASED
biological_processes:
- preferred_term: epidermal growth factor receptor signaling pathway
term:
id: GO:0007173
label: epidermal growth factor receptor signaling pathway
modifier: DECREASED
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Furthermore, we show that colorectal cancer patients treated with cetuximab, an antagonist of the EGFR, develop hypomagnesemia, emphasizing the significance of EGF in maintaining Mg(2+) balance."
explanation: >-
Pharmacologic EGFR blockade reproduces magnesium loss. This supports the
EGFR step by analogy; it is not an observation in the HOMG4 family.
downstream:
- target: Insufficient TRPM6 Activation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
EGFR stimulation activates TRPM6 through Src-family kinases and Rac1,
which move TRPM6 from intracellular stores to the plasma membrane, and
through ERK/AP-1, which raises TRPM6 transcription.
intermediate_mechanisms:
- Src-family kinase and Rac1 signaling
- ERK/AP-1 transcriptional activation
evidence:
- reference: PMID:19073827
reference_title: "EGF increases TRPM6 activity and surface expression."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In summary, EGF-mediated stimulation of TRPM6 occurs via signaling through Src kinases and Rac1, thereby redistributing endomembrane TRPM6 to the plasma membrane."
explanation: Identifies the signaling path from EGFR to TRPM6 surface expression.
- reference: PMID:19937979
reference_title: "Up-regulation of TRPM6 transcriptional activity by AP-1 in renal epithelial cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These results suggest that EGF up-regulates TRPM6 mRNA expression mediate via the activation of ERK/AP-1-dependent pathway."
explanation: A second, transcriptional route from EGF to TRPM6.
- name: Insufficient TRPM6 Activation
biological_scale: CELLULAR
description: >-
TRPM6 is the apical magnesium channel that carries transcellular magnesium
reabsorption in the DCT. Less EGF stimulation means less TRPM6 at the
apical surface and less magnesium entry from the tubular fluid.
cell_types:
- preferred_term: kidney distal convoluted tubule epithelial cell
term:
id: CL:1000849
label: kidney distal convoluted tubule epithelial cell
genes:
- preferred_term: TRPM6
term:
id: hgnc:17995
label: TRPM6
molecular_functions:
- preferred_term: magnesium ion transmembrane transporter activity
term:
id: GO:0015095
label: magnesium ion transmembrane transporter activity
modifier: DECREASED
biological_processes:
- preferred_term: magnesium ion transmembrane transport
term:
id: GO:1903830
label: magnesium ion transmembrane transport
modifier: DECREASED
locations:
- preferred_term: distal convoluted tubule
term:
id: UBERON:0001292
label: distal convoluted tubule
evidence:
- reference: PMID:19073827
reference_title: "EGF increases TRPM6 activity and surface expression."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Stimulation of the EGF receptor increased current through TRPM6 but not TRPM7."
explanation: EGFR stimulation specifically raises TRPM6 current.
downstream:
- target: Impaired DCT Magnesium Reabsorption
causal_link_type: DIRECT
description: >-
Reduced TRPM6-mediated reabsorption lets magnesium escape in the urine.
evidence:
- reference: PMID:17671646
reference_title: "When EGF is offside, magnesium is wasted."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: OTHER
snippet: "EGF stimulates Mg(2+) reabsorption in the renal distal convoluted tubule (DCT) via engagement of its receptor on the basolateral membrane of DCT cells and activation of the Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) in the apical membrane."
explanation: >-
A commentary summarizing the cascade from basolateral EGFR to apical
TRPM6 and magnesium reabsorption.
- name: Impaired DCT Magnesium Reabsorption
biological_scale: ORGANISM
description: >-
Urinary magnesium stays relatively high despite low serum magnesium,
which shows a tubular reabsorption defect. Magnesium infusion studies
showed a lowered renal threshold with a normal tubular maximum. Urinary
calcium is normal, which separates this disorder from the hypercalciuric
forms of renal magnesium wasting.
locations:
- preferred_term: distal convoluted tubule
term:
id: UBERON:0001292
label: distal convoluted tubule
biological_processes:
- preferred_term: magnesium ion homeostasis
term:
id: GO:0010960
label: magnesium ion homeostasis
modifier: ABNORMAL
evidence:
- reference: PMID:3436090
reference_title: "Isolated autosomal recessive renal magnesium loss in two sisters."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Magnesium infusion studies revealed a lowered threshold but a normal tubular maximum for magnesium."
explanation: Characterizes the renal handling defect in the affected sisters.
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Given the low serum Mg2+ levels, urinary Mg2+ excretion was relatively high, indicating a renal Mg2+ reabsorption defect."
explanation: Inappropriate urinary magnesium loss despite low serum levels.
downstream:
- target: Renal magnesium wasting
causal_link_type: DIRECT
description: The tubular defect is measured clinically as renal magnesium wasting.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Given the low serum Mg2+ levels, urinary Mg2+ excretion was relatively high, indicating a renal Mg2+ reabsorption defect."
explanation: Urinary magnesium is inappropriately high in both patients.
- target: Hypomagnesemia
causal_link_type: DIRECT
description: Continuing urinary loss lowers serum magnesium.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In short, 2 patients of this family, V3 and V4, had serum Mg2+ levels of 0.53 mM and 0.56 mM and urinary Mg2+ values of 3.9 mmol/24 h and 3.7 mmol/24 h, respectively."
explanation: Low serum magnesium alongside urinary losses in both sisters.
phenotypes:
- category: Metabolic
name: Hypomagnesemia
description: >-
Chronic low serum magnesium, 0.53 and 0.56 mM in the two sisters, with no
other electrolyte or acid-base abnormality.
phenotype_term:
preferred_term: Hypomagnesemia
term:
id: HP:0002917
label: Hypomagnesemia
temporality: CHRONIC
diagnostic: true
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In short, 2 patients of this family, V3 and V4, had serum Mg2+ levels of 0.53 mM and 0.56 mM and urinary Mg2+ values of 3.9 mmol/24 h and 3.7 mmol/24 h, respectively."
explanation: Serum magnesium values of both affected sisters.
- category: Renal
name: Renal magnesium wasting
description: >-
Urinary magnesium excretion is inappropriately high for the low serum
level, with normal urinary calcium.
phenotype_term:
preferred_term: Renal magnesium wasting
term:
id: HP:0005567
label: Renal magnesium wasting
diagnostic: true
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Given the low serum Mg2+ levels, urinary Mg2+ excretion was relatively high, indicating a renal Mg2+ reabsorption defect."
explanation: Inappropriate urinary magnesium loss.
- reference: PMID:3436090
reference_title: "Isolated autosomal recessive renal magnesium loss in two sisters."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In contrast to two families with the autosomal dominant form of isolated renal magnesium wasting, the calcium excretion in the urine was normal."
explanation: Urinary calcium excretion is normal, a distinguishing feature.
- category: Neurological
name: Seizure
description: >-
Epileptic seizures beginning in the first year of life, controlled with
conventional antiseizure drugs. The original clinical report judged them
unrelated to the hypomagnesemia, so no mechanism node points to this
phenotype.
phenotype_term:
preferred_term: Epileptic seizures
term:
id: HP:0001250
label: Seizure
onset:
onset_category: INFANTILE
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients suffer from epileptic seizures that started in their first year of life and are controlled by conventional antiepileptic drugs."
explanation: Seizures with onset in infancy in both sisters.
- reference: PMID:3436090
reference_title: "Isolated autosomal recessive renal magnesium loss in two sisters."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two children in this family suffered from convulsions unrelated to hypomagnesemia."
explanation: >-
Confirms convulsions in both children and records the clinicians'
judgement that they were not caused by the hypomagnesemia.
- category: Neurological
name: Global developmental delay
description: Psychomotor delay during childhood in both sisters.
phenotype_term:
preferred_term: Psychomotor retardation
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "During childhood, they showed psychomotor retardation, and they are presently moderately mentally retarded women."
explanation: Childhood psychomotor delay in both sisters.
- category: Neurological
name: Moderate intellectual disability
description: >-
Both sisters are moderately intellectually disabled as adults. Whether this
reflects a role of EGF in brain development, early seizures, or something
else is not known.
phenotype_term:
preferred_term: Moderate intellectual disability
term:
id: HP:0002342
label: Moderate intellectual disability
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "During childhood, they showed psychomotor retardation, and they are presently moderately mentally retarded women."
explanation: Moderate intellectual disability in adulthood.
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Moreover, it raises the question of whether EGF plays a role in mental development since our IRH patients (Figure 1A) are mentally retarded."
explanation: >-
The authors leave open whether EGF itself is involved in the
intellectual disability.
biochemical:
- name: Urinary calcium
presence: NORMAL
notes: >-
Serum and urinary calcium, sodium, potassium, chloride, bicarbonate, blood
pH, renin, aldosterone and parathyroid hormone were all normal, which marks
the magnesium loss as isolated.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Serum and urinary Ca2+ were in the normal range, as were serum Na+, K+, Cl–, HCO3–, and blood pH values."
explanation: Normal calcium and other electrolytes in both patients.
- name: Fractional excretion of magnesium
presence: INCREASED
notes: >-
Fractional magnesium excretion was inappropriately high for the low serum
magnesium in both sisters: 4.8% in V3 and 3.6% in V4, with serum magnesium
0.53-0.66 mM. A fractional excretion above 2% during hypomagnesemia
indicates renal magnesium loss.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two affected sisters, V3 and V4 (Figure 1A), displayed low serum Mg2+ levels (0.53-0.66 mM) in combination with urinary fractional excretion (FE) values of Mg2+ of 4.8% and 3.6%, respectively."
explanation: Gives the two patients' fractional magnesium excretion values, both above the 2% threshold.
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hypomagnesemia in combination with an inappropriately high excretion of Mg2+ was observed in patients with the P1070L mutation as well as in individuals treated with cetuximab."
explanation: Raised fractional magnesium excretion in the two patients.
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "As previously established by Agus (5), an FE of Mg2+ above 2% in the presence of hypomagnesemia indicates renal Mg2+ loss."
explanation: The diagnostic threshold for renal magnesium loss, cited from earlier work.
genetic:
- name: EGF
gene_term:
preferred_term: EGF
term:
id: hgnc:3229
label: EGF
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
features: >-
EGF (4q25) encodes pro-epidermal growth factor, a type I membrane precursor
processed to the 53-amino-acid EGF peptide. In the DCT it acts as a local
magnesiotropic hormone. Only one disease allele is known.
notes: >-
The gene-disease link rests on one family. Other known causes of isolated
renal magnesium wasting (SLC12A3, CLDN16, FXYD2 and TRPM6) were excluded in
the two sisters before EGF was found.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Through the discovery of a mutation in the EGF gene in isolated autosomal recessive renal hypomagnesemia, we have, for what we believe is the first time, identified a magnesiotropic hormone crucial for total body Mg(2+) balance."
explanation: Identifies EGF as the causal gene.
variants:
- name: NM_001963.6:c.3209C>T (p.Pro1070Leu)
type: MISSENSE
clinical_significance: PATHOGENIC
description: >-
Homozygous in both affected sisters and absent from 126 ethnically
matched control chromosomes.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected individuals both have a homozygous mutation C3209T in exon 22, resulting in the amino acid substitution P1070L."
explanation: Reports the variant and zygosity.
treatments:
- name: Antiseizure medication
description: >-
Seizures in both sisters are controlled with conventional antiseizure
drugs. The specific agents are not named in the source.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: anticonvulsant therapy
term:
id: NCIT:C64172
label: Anticonvulsant Therapy
target_phenotypes:
- preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients suffer from epileptic seizures that started in their first year of life and are controlled by conventional antiepileptic drugs."
explanation: Seizures respond to standard antiseizure drugs.
experimental_models:
- name: Polarized MDCK cells expressing wild-type or p.Pro1070Leu pro-EGF
experimental_model_type: CELL_LINE
description: >-
Filter-grown MDCK cells expressing wild-type or mutant pro-EGF, with
apical and basolateral media tested for their ability to stimulate TRPM6
current in HEK293 cells.
publication: PMID:17671655
modeled_mechanisms:
- target: Impaired Basolateral Sorting of Pro-EGF
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Mutant pro-EGF fails to deliver TRPM6-stimulating activity to the
basolateral medium.
limitations: >-
MDCK is a canine kidney line, and TRPM6 activity is read out in a
separate HEK293 overexpression system rather than in DCT cells.
evidence:
- reference: PMID:17671655
reference_title: "Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "However, stimulation of TRPM6 channel activity was only observed with basolaterally collected wild-type pro-EGF medium, not with the basolateral mutant pro-EGF media (Figure 3E)."
explanation: The cell model reproduces the sorting defect.
discussions:
- discussion_id: no_animal_model_of_egf_p1070l
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Impaired Basolateral Sorting of Pro-EGF
- pathophysiology#Inadequate Renal EGFR Stimulation
prompt: >-
Does p.Pro1070Leu cause renal magnesium wasting in a whole animal, and does
loss of EGF alone do so?
rationale: >-
The mechanism rests on one family and on cell assays: MDCK sorting and
HEK293 TRPM6 currents. No animal carrying p.Pro1070Leu has been reported,
so the step from missorted pro-EGF to kidney magnesium loss has not been
shown in vivo. The deep-research report says Egf-knockout mice do not
become hypomagnesemic, which would argue that the variant does more than
remove EGF, but its citation for that statement did not resolve and no
source for it was found (searches listed in the entry notes), so the
statement is not curated. Whether the mouse is a valid model therefore
stays an open question rather than a recorded mismatch.
proposed_experiments:
- experiment_id: egf_p1070l_knockin_mouse
name: Egf p.Pro1070Leu knock-in mouse
description: >-
Knock the patient variant into mouse Egf and measure serum magnesium,
fractional magnesium excretion, and apical TRPM6 in the distal
convoluted tubule, alongside an Egf-null line.
would_support:
- pathophysiology#Impaired Basolateral Sorting of Pro-EGF
supporting_outcome:
- Knock-in mice waste magnesium in the urine and show less apical TRPM6 in the distal convoluted tubule.
refuting_outcome:
- Knock-in mice keep normal serum magnesium and fractional excretion.
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.
Review round 1: evidence grading, knockout gap, FEMg · 2026-10-15T09:31:09Z · View source
Answers the review on PR 14307. Two abstract sentences from PMID:17671655 that summarize the MDCK and HEK293 assays were re-graded from HUMAN_CLINICAL to IN_VITRO, the second also marked directness INDIRECT. The deep-research report's claim that Egf-knockout mice do not become hypomagnesemic could not be sourced: its citation does not resolve, and PubMed and Europe PMC searches (recorded verbatim in the entry notes, re-run before commit) returned no such study. The claim was therefore not curated, and a KNOWLEDGE_GAP discussion records that no animal model of p.Pro1070Leu exists, with a proposed knock-in experiment; HUMAN_MODEL_MISMATCH was not used because it would assert model evidence that could not be cited. The node Renal Magnesium Wasting was renamed Impaired DCT Magnesium Reabsorption so it no longer differs from the phenotype only in case. A biochemical row for raised fractional magnesium excretion was added; the patients' values appear only in a figure, so no number is curated. Brisk reflexes were not added because the 2007 full text does not mention reflexes. The trailing-whitespace change to references_cache/PMID_17671655.md was reverted to the fetched bytes, and a description was added to the EGF receptor binding descriptor.
Create: Renal Hypomagnesemia 4 · 2026-10-15T08:02:52Z · View source
New entry for renal hypomagnesemia 4 (MONDO:0012717, EGF). Source report: research/Renal_Hypomagnesemia_4-deep-research-perplexity.md (Perplexity sonar-deep-research, default reasoning effort); 16/16 references resolved. preflight-dr returned WARN because its heuristic gene lexicon counted the disease abbreviation HOMG4 as a second gene; the report names OMIM 611718 and EGF throughout. Primary sources: the 2007 molecular report (PMID:17671655, full text cached) and the 1987 clinical report (PMID:3436090), plus two mechanism papers (PMID:19073827, PMID:19937979) and a commentary (PMID:17671646), found by PubMed search. The report presents the seizures as caused by hypomagnesemia, but PMID:3436090 states the convulsions were unrelated to hypomagnesemia, so seizures and intellectual disability are curated without an incoming edge from the magnesium chain. Magnesium replacement is not curated because no cited source reports it in these patients. Validated with just validate, count-verified-snippets (30/30), validate-terms, check-genereviews (NO_CHAPTER) and check-causal-targets.
Disease: Renal hypomagnesemia 4
Preferred molecular designation: EGF-related primary renal hypomagnesemia with intellectual disability
MONDO: MONDO:0012717
Disease class: Mendelian renal tubular magnesium-transport disorder
Evidence status: Exceptionally rare; the molecularly confirmed human evidence remains limited to two affected sisters from one consanguineous Dutch family. Consequently, apparent phenotype frequencies of 100% are not reliable population estimates. OMIM itself marks the phenotype with a question mark, reflecting the limited genetic evidence. [392]
Renal hypomagnesemia 4 (HOMG4) is an autosomal-recessive disorder in which defective basolateral targeting of pro-epidermal growth factor impairs EGF–EGFR stimulation of the apical magnesium channel TRPM6 in distal convoluted tubule cells. The resulting failure of renal magnesium conservation causes chronic hypomagnesemia, infantile generalized seizures, developmental delay, and moderate intellectual disability, while serum calcium and urinary calcium are characteristically normal. [113][391]
The landmark molecular study identified homozygous EGF c.3209C>T, p.(Pro1070Leu) in the two sisters. Its abstract summarized the core mechanism as: “The mutation leads to impaired basolateral sorting of pro-EGF.” It further linked inadequate renal EGFR stimulation to insufficient TRPM6 activation and magnesium loss. Human clinical, cell-biological, electrophysiologic, and pharmacologic evidence were included in that report. PMID: 17671655; DOI: 10.1172/JCI31680; published August 1, 2007. [113]
| Identifier/system | Identifier or name | Notes |
|---|---|---|
| MONDO | MONDO:0012717 | Renal hypomagnesemia 4 |
| OMIM phenotype | 611718 | Hypomagnesemia 4, renal; HOMG4 |
| OMIM gene | 131530 | EGF |
| Disease Ontology | DOID:0060882 | Renal hypomagnesemia 4 |
| Current Orphanet disease | ORPHA:620368 | EGF-related primary hypomagnesemia with intellectual disability; prevalence listed as <1/1,000,000 |
| Historical Orphanet mapping | ORPHA:34527 | Familial primary hypomagnesemia with normocalciuria and normocalcemia; now obsolete/group-level terminology |
| ICD-10-CM | E83.4 | Disorders of magnesium metabolism; not disease-specific |
| ICD-11 | GB90.4Y | Other specified renal tubular dysfunction |
| MeSH | D008275, Magnesium Deficiency | No disease-specific MeSH descriptor; D008274 denotes magnesium itself |
| SNOMED CT | 80710001 | Primary hypomagnesemia; broader concept |
| UMLS | C5681825 | EGF-related primary hypomagnesemia with intellectual disability |
| Gene | HGNC:3229; NCBI Gene:1950; ENSG00000138798 | EGF, chromosome 4q25 |
| Protein | UniProt P01133 | Pro-epidermal growth factor |
The current Orphanet entry gives infancy/childhood onset, absence of secondary hypocalcemia and obesity, and prevalence below one per million. [134] The DO definition and historical ontology cross-references include OMIM 611718, ICD-10-CM E83.4, and ORDO:34527. [391]
| Synonym/alternative name | Comment |
|---|---|
| Hypomagnesemia 4, renal | OMIM name |
| HOMG4 | Abbreviation |
| Renal hypomagnesemia type 4 | Common alternative |
| Isolated recessive renal hypomagnesemia | Historical clinical name |
| Autosomal-recessive isolated renal magnesium loss | Descriptive name |
| EGF-related primary hypomagnesemia | Molecular name |
| EGF familial primary hypomagnesemia | MONDO/NORD synonym |
| EGF-related primary hypomagnesemia with intellectual disability | Current Orphanet name |
| Normocalciuric renal hypomagnesemia due to EGF | Biochemical description |
These synonyms are consolidated in MONDO-linked resources and the current/historical Orphanet nomenclature. [394]
The disease entry is based on:
It is not based on an EHR cohort, population registry, randomized trial, or broad natural-history series.
The established initiating lesion is homozygosity for the germline missense variant:
NM_001963.6(EGF):c.3209C>T; NP_001954.2:p.(Pro1070Leu); rs121434567.
The substitution affects the second proline in the cytoplasmic PKNP/PXXP basolateral-sorting motif of pro-EGF. It disrupts basolateral—but not apical—delivery/release in polarized epithelial cells. [257]
| Factor class | Evidence and interpretation |
|---|---|
| Biallelic EGF p.Pro1070Leu | Primary demonstrated genetic cause; both affected sisters were homozygous |
| Heterozygosity | Parents, two unaffected sisters, and a paternal aunt were unaffected carriers, supporting recessive inheritance |
| Consanguinity | Parents were second cousins; increased the probability of homozygosity for the rare allele |
| Family history | Affected sibling or known carrier parents substantially increases Mendelian recurrence risk |
| Sex | No evidence of sex dependence; both known patients happened to be female |
| Age | Congenital genotype, with manifestations beginning in infancy |
| Low magnesium intake or gastrointestinal loss | Not causal, but expected to worsen magnesium depletion because renal conservation is impaired |
| Magnesium-wasting drugs | Diuretics, cisplatin, aminoglycosides, calcineurin inhibitors, and especially EGFR inhibitors may aggravate the biochemical defect |
| Alcohol misuse | Can worsen magnesium deficiency through low intake, gastrointestinal loss, and renal wasting |
| Adequate magnesium intake/replacement | Reduces deficiency and complication risk but does not correct the inherited trafficking defect |
| Genetic protective variants | None reported |
| Modifier genes | None established |
Loop and thiazide diuretics increase urinary magnesium loss, while prolonged PPI treatment, poor intake, alcoholism, and gastrointestinal disease may further lower magnesium status. [333] EGFR inhibitors are especially mechanistically relevant because cetuximab, panitumumab, and related drugs reproduce renal magnesium wasting by interrupting the same pathway. [336]
The genotype reduces the kidney’s reserve capacity to conserve magnesium. Accordingly, low dietary intake, diarrhea, vomiting, alcohol-associated depletion, or magnesium-wasting medication should produce a larger fall in serum magnesium than in an unaffected person. This interaction is physiologically plausible but has not been studied directly in HOMG4 patients.
Conversely, dietary magnesium restriction induces compensatory renal TRPM6 expression in wild-type mice; that compensation may be inadequate when upstream EGF–EGFR signaling is defective. [310]
No infectious, toxic, occupational, radiation, or immune cause of the Mendelian disorder has been identified.
Frequencies below refer to the only two published molecularly confirmed patients and therefore must not be interpreted as robust estimates.
| Phenotype | Type | Onset/course/severity | Reported frequency | Suggested HPO term | Functional or quality-of-life impact |
|---|---|---|---|---|---|
| Hypomagnesemia, serum 0.53–0.66 mmol/L | Laboratory abnormality | Chronic; moderate-to-severe | 2/2 | HP:0002917 Hypomagnesemia | Requires lifelong monitoring and likely replacement; predisposes to neurologic and cardiac complications |
| Inappropriate renal magnesium excretion | Laboratory/renal sign | Lifelong; persistent | 2/2 | HP:0005567 Renal magnesium wasting | Makes correction more difficult despite low serum magnesium |
| Fractional Mg excretion 4.8% and 3.6% | Laboratory abnormality | Persistent in tested adults | 2/2 | HP:0005567 | Confirms impaired tubular conservation |
| Generalized epileptic seizures | Neurologic symptom | Began in first year of life; recurrent but controlled with conventional antiseizure drugs | 2/2 | HP:0001250 Seizure; more specific HP:0002197 Generalized-onset seizure | Acute danger, medication burden, restrictions on activities |
| Psychomotor/global developmental delay | Developmental manifestation | Childhood; persistent | 2/2 | HP:0001263 Global developmental delay or HP:0011343 Moderate global developmental delay | Delayed acquisition of motor/cognitive skills |
| Moderate intellectual disability | Behavioral/neurodevelopmental manifestation | Adult outcome; stable/chronic | 2/2 | HP:0002342 Intellectual disability, moderate | Lifelong limitations in independent living, education, employment, and communication |
| Brisk tendon reflexes | Clinical neurologic sign | Reported in original family | 2/2 reported collectively | HP:0001348 Brisk reflexes | Marker of neuromuscular excitability; direct daily impact uncertain |
| Tetany | Neuromuscular symptom | Included in current Orphanet disease description, but not clearly documented in the two sisters | Unknown | HP:0001281 Tetany | Painful spasms and acute functional impairment if present |
| Normocalcemia | Negative laboratory feature | Persistent in reported family | 2/2 | No abnormal HPO term; record as “hypocalcemia absent” | Distinguishes HOMG4 from TRPM6-related hypomagnesemia with secondary hypocalcemia |
| Normocalciuria | Negative/differentiating laboratory feature | Persistent | 2/2 | No abnormal HPO term | Distinguishes hypercalciuric renal hypomagnesemias |
| Normal Na, K, Cl, bicarbonate, pH, PTH, renin and aldosterone | Negative laboratory features | At evaluation | 2/2 where assessed | Record as excluded findings | Supports an isolated magnesium-handling defect |
| Infantile onset | Temporal qualifier | First-year seizure onset | 2/2 | HP:0003593 Infantile onset | Defines a critical period for early diagnosis and prevention of recurrent seizures |
The original clinical observations included seizures, mild-to-moderate psychomotor retardation and brisk reflexes. [153] The molecular reassessment documented serum magnesium of 0.53–0.66 mmol/L and fractional magnesium excretion of 4.8% and 3.6%. [164]
It remains uncertain whether developmental impairment results entirely from early, recurrent hypomagnesemic seizures or whether altered EGF signaling contributes directly to brain development. The original study detected EGF expression in human cerebrum, but no patient neuroimaging, neuropathology, or brain-specific functional study established a direct developmental mechanism. Therefore:
No disease-specific EQ-5D, SF-36, PROMIS, educational, caregiver-burden, or other quality-of-life data are available.
| Attribute | Value |
|---|---|
| Gene symbol | EGF |
| Name | Epidermal growth factor |
| HGNC | HGNC:3229 |
| NCBI Gene | 1950 |
| Ensembl | ENSG00000138798 |
| OMIM gene | 131530 |
| Cytogenetic location | 4q25 |
| GRCh38 coordinates | chr4:109,912,883–110,013,766 |
| Exons | 24 |
| Canonical/MANE transcript | NM_001963.6 |
| Protein | Pro-epidermal growth factor |
| UniProt | P01133 |
| Protein class/localization | Single-pass type-I membrane precursor, proteolytically processed to a 53-amino-acid mature EGF peptide |
NCBI describes EGF as a precursor processed into a 53-amino-acid peptide that binds EGFR and regulates cellular proliferation and differentiation. [91] UniProt records p.Pro1070Leu as affecting basolateral sorting and preventing effective EGFR/TRPM6 stimulation. [94]
| Feature | Detail |
|---|---|
| Variant | NM_001963.6:c.3209C>T |
| Protein | NP_001954.2:p.(Pro1070Leu) |
| Genomic GRCh38 | NC_000004.12:g.110004540C>T |
| Genomic GRCh37 | NC_000004.11:g.110925696C>T |
| dbSNP | rs121434567 |
| ClinVar | Variation ID 16614; VCV000016614.1 |
| Variant type | Germline missense SNV |
| Zygosity in patients | Homozygous |
| ClinVar classification | Pathogenic, one literature-only submission |
| Review status | No expert-panel review; no modern ACMG criteria supplied |
| Last formal evaluation | August 1, 2007 |
| gnomAD frequency | Approximately 0.00003 overall; exomes approximately 0.00002 |
| ExAC frequency | Approximately 0.00003 |
| TOPMed frequency | Approximately 0.00001–0.00002 |
| Functional consequence | Defective polarized sorting/processing and basolateral secretion of pro-EGF; functional loss of local EGF–EGFR signaling |
| Controls in original study | Absent from 126 ethnically matched control chromosomes |
The complete ClinVar record confirms the coordinates, frequencies and single literature-only pathogenic submission. [106] The very low population frequency is compatible with recessive disease, but ClinVar’s classification is not an expert-panel or multi-laboratory consensus.
Both affected sisters were homozygous. Both parents, two unaffected sisters, and a paternal aunt were heterozygous; two children of the aunt were homozygous reference. This is consistent with high penetrance for the homozygous state and nonpenetrance in heterozygotes, but only two homozygotes are known.
No data establish:
Assuming Hardy–Weinberg equilibrium and an allele frequency of 2–3×10⁻⁵, a purely illustrative carrier frequency would be about 4–6×10⁻⁵ and homozygous frequency approximately 4–9×10⁻¹⁰. This estimate is uncertain because ancestry-specific frequency, pathogenicity, ascertainment, and founder effects are inadequately characterized.
Renal hypomagnesemia 4 is genetic, not environmentally caused. Clinically relevant exacerbating factors include:
| Environmental/lifestyle factor | Expected effect |
|---|---|
| Magnesium-poor diet or malnutrition | Reduces available magnesium and worsens depletion |
| Chronic diarrhea, malabsorption, vomiting | Adds gastrointestinal magnesium loss |
| Alcohol misuse | Combines inadequate intake, gastrointestinal loss and renal wasting |
| Loop/thiazide diuretics | Increase urinary magnesium excretion |
| Cisplatin/carboplatin, aminoglycosides, amphotericin B, calcineurin inhibitors | Cause tubular magnesium wasting |
| Cetuximab, panitumumab, erlotinib and other EGFR antagonists | Directly interfere with the same EGF–EGFR–TRPM6 axis |
| Long-term proton-pump inhibitors | Mainly reduce intestinal magnesium absorption |
| Adequate dietary magnesium and avoidance of avoidable magnesium-wasting drugs | Protective against biochemical deterioration, not against inheritance |
There is no evidence for smoking, exercise, pollution, radiation, occupational exposure, or infectious-agent involvement specific to HOMG4.
The 2007 study showed:
A later primary study reported that EGFR activation recruits Src-family kinases and Rac1, redistributing vesicular TRPM6 to the plasma membrane. PMID associated with JASN 2009; DOI 10.1681/ASN.2008030327. [241] Another study found EGF-dependent increases in phospho-ERK1/2, c-Fos, c-Jun and TRPM6 transcription, supporting an ERK/AP-1 branch; PMID 19937979, published online November 2009. [244]
Recent renal-magnesium reviews continue to place EGF upstream of TRPM6/TRPM7-mediated DCT reabsorption. A 2023 review states that EGF increases TRPM6 membrane expression and transcription and acts as a paracrine DCT regulator. [232] The 2024 Core Curriculum similarly describes DCT magnesium reabsorption through TRPM6/TRPM7 heteromers and paracrine regulation by EGF. [228]
However, complete Egf knockout mice do not develop significant hypomagnesemia, indicating species differences, ligand redundancy, developmental compensation, or a variant effect more complex than simple EGF absence. [305] Thus, the human p.Pro1070Leu mechanism is best described as abnormal polarized pro-EGF sorting/processing, not proven generic EGF haploinsufficiency.
| Mechanistic feature | Suggested ontology term |
|---|---|
| Magnesium-ion homeostasis | GO:0010960 |
| ERBB signaling | GO:0038127 |
| EGF receptor signaling | GO:0007173, noting that current GO marks this term obsolete in favor of broader/current descendants |
| Protein localization to plasma membrane | GO:0072659 |
| Vesicle-mediated transport | GO:0016192 |
| Magnesium-ion transmembrane transport | GO:1903830 |
| EGF receptor binding | GO:0005154 |
| Apical plasma membrane | GO:0016324 |
| Basolateral plasma membrane | GO:0016323 |
| Plasma membrane | GO:0005886 |
| Magnesium ion | CHEBI:18420 |
| DCT epithelial cell | CL:1000849 |
| Early DCT epithelial cell | CL:4030016 |
The correct DCT epithelial-cell identifier is CL:1000849. [196] GO:0010960 denotes magnesium-ion homeostasis, while GO:0016323 and GO:0016324 identify basolateral and apical plasma membranes. [426][427]
No HOMG4-specific patient transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, organoid, iPSC or integrated multi-omics study was found. Current single-cell kidney atlases recognize DCT epithelial cells and markers such as SLC12A3 and TRPM6, but this is normal-reference annotation rather than disease profiling. [206]
| Level | Structure/cell/compartment | Role and suggested ontology |
|---|---|---|
| Primary organ | Kidney | Direct site of magnesium wasting; UBERON:0002113 |
| Primary segment | Distal convoluted tubule | Final fine-tuning of urinary magnesium; UBERON:0001292 |
| Primary cell | DCT epithelial cell | CL:1000849 |
| Basolateral compartment | Basolateral plasma membrane | Pro-EGF targeting and EGFR localization; GO:0016323 |
| Apical compartment | Apical plasma membrane | TRPM6/TRPM7 channel localization; GO:0016324 |
| Secondary system | Central nervous system | Seizures and developmental/cognitive phenotype; direct EGF effect not established |
| Secondary tissue | Skeletal muscle/neuromuscular system | Potential tetany and hyperreflexia caused by systemic magnesium deficiency |
| Secondary system | Cardiovascular conduction system | Potential arrhythmia risk from severe hypomagnesemia; not reported in HOMG4 |
| Gastrointestinal tract | Not primarily defective | Original retention studies indicated preserved intestinal absorption |
The DCT corresponds to UBERON:0001292 and its epithelial cells to CL:1000849. [202][200] The disease is systemic and bilateral by virtue of a germline defect; unilateral or asymmetric renal involvement is not expected.
No formal natural-history staging system or longitudinal cohort exists.
| Characteristic | Best available evidence |
|---|---|
| Inheritance | Autosomal recessive |
| Known affected individuals | 2 sisters |
| Known families | 1 consanguineous Dutch family |
| Sex ratio | 0 male:2 female; not interpretable |
| Prevalence | Orphanet: <1 per 1,000,000 |
| Incidence | Unknown |
| Geographic distribution | Original family from the Netherlands; rare population-database alleles occur more broadly, but ancestry distribution is not adequately reported |
| Penetrance | 2/2 known homozygotes affected; true penetrance unknown |
| Expressivity | Similar in the sisters; broader variability unknown |
| Carrier phenotype | Five identified heterozygotes were unaffected with respect to hypomagnesemia |
| Consanguinity | Important in the only family; parents were second cousins |
| Anticipation | Not applicable/reported |
| Germline mosaicism | Not reported |
| Founder effect | Not established |
| Carrier frequency | Unknown; rough p.Pro1070Leu frequency-based estimate 1 in 17,000–25,000, subject to major uncertainty |
| Population screening | Not justified given extreme rarity and insufficient prevalence data |
Current Orphanet prevalence is below one per million. [134] A review emphasizes that only two affected girls from one consanguineous family have been reported. [380]
For two carrier parents, standard autosomal-recessive recurrence probabilities are 25% affected, 50% carrier, and 25% unaffected/noncarrier per pregnancy, assuming both parental variants are confirmed and fully penetrant.
[ FE_{Mg}=\frac{U_{Mg}\times P_{Cr}}{0.7\times P_{Mg}\times U_{Cr}}\times100 ]
| Test | Utility |
|---|---|
| Renal tubulopathy/hypomagnesemia multigene panel | Preferred first-line genetic test; should include EGF, TRPM6, CNNM2, FXYD2, SLC12A3, CLDN16, CLDN19, KCNA1, KCNJ10, HNF1B, ATP1A1, RRAGD and related genes |
| EGF sequencing | Appropriate when phenotype is isolated normocalciuric renal Mg wasting with recessive inheritance |
| Deletion/duplication analysis | Reasonable if sequencing is negative; no HOMG4-causing deletion is currently established |
| WES | Useful for atypical cases or negative panel testing |
| WGS | Useful for deep-intronic, regulatory or structural variants and reanalysis; clinical yield for HOMG4 is unknown |
| RNA sequencing | Research/functional option for suspected splice variants; no established diagnostic assay |
| CMA | Low expected yield for an isolated single-gene phenotype; useful if syndromic features suggest a genomic imbalance |
| Karyotype/FISH | Not routinely indicated |
| Mitochondrial DNA testing | Not indicated unless another phenotype suggests mitochondrial disease |
| Repeat-expansion testing | Not relevant |
| Prenatal/PGT-M testing | Technically possible once familial pathogenic variants are established |
Orphanet lists postnatal molecular testing panels containing EGF and other primary-hypomagnesemia genes. [126]
| Differential | Distinguishing findings |
|---|---|
| TRPM6-related hypomagnesemia with secondary hypocalcemia | Much more severe Mg deficiency, impaired intestinal absorption, secondary hypocalcemia |
| CNNM2-related hypomagnesemia | Usually dominant/de novo or semidominant; seizures, intellectual disability, obesity or brain abnormalities may occur |
| Gitelman syndrome, SLC12A3 | Hypokalemia, metabolic alkalosis and hypocalciuria |
| FXYD2 hypomagnesemia | Usually autosomal dominant; hypocalciuria may occur |
| CLDN16/CLDN19 disease | Hypercalciuria, nephrocalcinosis, progressive kidney disease; ocular abnormalities with CLDN19 |
| EAST/SeSAME, KCNJ10 | Epilepsy, ataxia, sensorineural deafness and salt-wasting tubulopathy |
| KCNA1 disease | Episodic ataxia and renal magnesium wasting |
| HNF1B-associated disease | Renal malformations/cysts, diabetes, genital anomalies and hypomagnesemia |
| EGFR-related epithelial inflammatory syndrome | Severe skin/gut epithelial inflammation in addition to hypomagnesemia |
| Drug-induced renal Mg wasting | Exposure history; improvement after withdrawal where possible |
| Gastrointestinal loss/PPI-associated deficiency | Low urinary magnesium or FEMg generally <2% |
| Malnutrition/alcohol-related depletion | Clinical context and mixed intake/GI/renal mechanisms |
The combination of urine/serum biochemistry, inheritance and extrarenal manifestations guides differential testing. Hypercalciuria suggests TAL disorders, whereas hypokalemia and metabolic alkalosis suggest Gitelman-like DCT disease. [319]
No newborn screening program or standardized clinical diagnostic criteria exist. Cascade biochemical and genetic testing is appropriate for relatives.
Disease-specific survival, mortality, five-year survival and life-expectancy statistics are unavailable. Both original patients survived into adulthood, suggesting that the condition is not inevitably fatal when seizures and electrolyte abnormalities are managed.
Important morbidity includes:
Severe hypomagnesemia can cause torsades de pointes and other fatal arrhythmias, although none were documented in the HOMG4 sisters. [346]
Prognostic factors are inferred to include:
No validated prognostic biomarker or disease-specific quality-of-life instrument exists. Serum magnesium, FEMg, seizure frequency, EEG findings and developmental trajectory are practical monitoring endpoints.
No treatment corrects the inherited pro-EGF trafficking defect. Management is supportive and extrapolated largely from general hypomagnesemia and other renal magnesium-wasting disorders.
| Intervention | Role/mechanism | Evidence in HOMG4 | Suggested ontology |
|---|---|---|---|
| Oral magnesium salts | Replace ongoing magnesium loss; chloride, lactate or other sustained-release preparations may be better absorbed/tolerated than oxide | No disease-specific response data reported | NCIT: magnesium supplementation; magnesium oxide NCIT:C29242 |
| IV magnesium sulfate | Acute treatment for severe symptomatic hypomagnesemia, seizures or arrhythmia | General standard, not specifically studied in HOMG4 | NCIT:C623; CHEBI:32599 |
| Subcutaneous magnesium sulfate | Slow outpatient replacement in refractory renal wasting | Evidence from unrelated refractory cases, not HOMG4 | NCIT:C623 |
| Amiloride | ENaC blockade can reduce renal magnesium loss | No HOMG4-specific trial; case-level evidence in idiopathic renal Mg wasting | Amiloride hydrochloride NCIT:C47390 |
| Antiseizure medication | Controls recurrent seizures | Conventional antiseizure drugs controlled seizures in both sisters | NCIT pharmacologic substance terms for the selected agent |
| Dietitian-guided magnesium-rich diet | Adjunct; cannot overcome substantial renal wasting alone | Not specifically studied | NCIT dietary intervention |
| Avoidance of magnesium-wasting medications | Prevents additive renal/GI loss | Mechanistically justified | NCIT medication review/supportive care |
| Developmental, educational, PT/OT and speech support | Addresses lifelong neurodevelopmental morbidity | No formal outcomes reported | NCIT rehabilitation/occupational therapy/speech therapy |
For acute unstable adult hypomagnesemia, general guidance uses 1–2 g magnesium sulfate over approximately 15 minutes, while nonemergent replacement may use 4–8 g over 12–24 hours; pediatric dosing requires weight-based specialist protocols. [165] Oral therapy is generally divided to reduce diarrhea, with careful dose reduction and monitoring when eGFR is below 30 mL/min/1.73 m².
Amiloride raised serum magnesium, lowered FEMg and improved symptoms in one patient with idiopathic renal magnesium wasting, but this is indirect evidence. [287] Continuous home subcutaneous magnesium sulfate at 2 g/day normalized or nearly normalized serum magnesium in a refractory renal-wasting case, again not HOMG4-specific. [176]
No registered HOMG4-specific interventional trial, gene therapy, RNA therapy, CRISPR treatment, cell therapy or recombinant EGF treatment was identified. Systemic EGF or EGFR agonism would carry substantial proliferative and oncologic concerns and is not an established treatment.
A future precision approach would require kidney/DCT-targeted restoration of correctly polarized EGF signaling or enhancement of TRPM6 surface expression without systemic mitogenic EGFR activation. This remains conceptual.
The inherited genotype cannot be prevented after conception. Reproductive options include:
No vaccine, antimicrobial prophylaxis, public-health sanitation intervention or population newborn-screening program applies.
| Species | Taxon/ortholog information | Natural disease evidence |
|---|---|---|
| Human, Homo sapiens | NCBI Taxon 9606; EGF Gene 1950 | Confirmed HOMG4 |
| Mouse, Mus musculus | Taxon 10090; Egf Gene 13645, MGI:95290 | No naturally occurring HOMG4 equivalent identified |
| Rat, Rattus norvegicus | Taxon 10116; Egf Gene 25313 | Kidney EGF localization used experimentally; no natural HOMG4 |
| Zebrafish, Danio rerio | Taxon 7955; egf Gene 403045 | Conserved ortholog; no reported natural HOMG4 |
| Dog, Canis lupus familiaris | Taxon 9615; EGF Gene 403657 | No EGF-related hereditary renal hypomagnesemia found |
| Cat, Felis catus | Taxon 9685; EGF Gene 493978 | No EGF-related hereditary renal hypomagnesemia found |
MGI records one-to-one vertebrate orthology among human, mouse, rat and zebrafish and mouse Egf NCBI Gene 13645. [271] No OMIA entry, breed predisposition, veterinary founder variant, zoonotic transmission or cross-species infectious risk was identified. The mechanism is evolutionarily relevant but the specific human disease does not appear to be a recognized natural veterinary disorder.
| Model | Type | Main finding | Strengths | Limitations |
|---|---|---|---|---|
| HEK293 expressing TRPM6 | In-vitro human cell system | EGF dose-dependently increased TRPM6 current; mutant-conditioned medium failed to stimulate it | Direct electrophysiology and EGFR blockade | Not a polarized DCT cell |
| Polarized MDCK-I cells expressing WT or p.Pro1070Leu pro-EGF | In-vitro canine kidney epithelium | Mutant retained apical release but lacked effective basolateral release | Demonstrates polarized sorting defect | Nonhuman cell line; overexpression |
| Rat kidney immunohistochemistry | Tissue model | EGF colocalized with NCC-positive DCT segments | Anatomical localization | Not a genetic disease model |
| Cetuximab-treated cancer patients | Human pharmacologic phenocopy | EGFR blockade caused renal magnesium wasting | Human in-vivo support for pathway | Acquired drug effect, different initiating lesion |
| Egf knockout mouse | Mammalian genetic model | No significant hypomagnesemia at 2 or 4 months | Tests complete ligand deficiency | Does not reproduce p.Pro1070Leu polarized-sorting defect; compensation/redundancy likely |
| Anti-EGFR-treated mouse | Induced mammalian model | Mild hypomagnesemia reported after antibody treatment | Tests receptor blockade | Urinary Mg response was limited; drug model rather than disease |
| TRPM6-deficient models | Downstream pathway models | Demonstrate the importance of TRPM6 to epithelial magnesium handling | Mechanistically relevant | Model a different human disorder and show tissue/species-dependent phenotypes |
| Patient-derived iPSC/DCT organoid | Not yet reported | Potential future model | Could examine human polarized trafficking in native genotype | Currently unavailable |
| Egf p.Pro1070Leu knock-in mouse | Not identified | Potential future model | Closest genetic test of the human lesion | Species may still fail to reproduce human renal phenotype |
The absence of hypomagnesemia in Egf knockout mice is a major model limitation and argues for creation of a precise p.Pro1070Leu knock-in, rather than assuming that complete knockout is equivalent to the human trafficking mutation. [305]
No new molecularly confirmed HOMG4 family or independently validated pathogenic EGF allelic series was found through the 2023–2024 literature. Recent work instead strengthens and refines the broader renal-magnesium framework:
The clinical phenotype and biochemical defect are well documented in two related humans, and the original p.Pro1070Leu functional experiments provide a coherent mechanism. Nevertheless, the gene–disease relationship remains constrained by a single family, a single variant, no independent replication, an old single-submitter ClinVar assertion, and a discordant Egf-knockout mouse phenotype. The best current interpretation is therefore:
Renal hypomagnesemia 4 is a highly plausible, functionally supported autosomal-recessive pro-EGF polarized-trafficking disorder, but its full allelic spectrum, penetrance, epidemiology, natural history and optimal treatment remain undetermined.
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 16 |
| Resolved | 16 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 16 |
| On topic | 11 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 38 |
| Resolved | 32 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 6 |
| Terms whose name was checked | 15 |
| Terms named correctly | 8 |
| Terms named as a different term | 4 |
| Terms whose name is worth a second look | 3 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0012717 (2 mentions) - the report calls it "MONDO"; MONDO calls it renal hypomagnesemia 4DOID:0060882 (1 mention) - the report calls it "Disease Ontology"; DOID calls it renal hypomagnesemia 4CL:4030016 (1 mention) - the report calls it "Early DCT epithelial cell"; CL calls it epithelial cell of early distal convoluted tubuleNCIT:C623 (2 mentions) - the report calls it "Evidence from unrelated refractory cases, not HOMG4"; NCIT calls it Magnesium SulfateThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0005154 (1 mention) - the report calls it "EGF receptor binding"; GO calls it epidermal growth factor receptor binding, and lists "EGF receptor binding" among its other namesCHEBI:18420 (1 mention) - the report calls it "Magnesium ion"; CHEBI calls it magnesium(2+), and lists "MAGNESIUM ION" among its other namesCL:1000849 (4 mentions) - the report calls it "DCT epithelial cell"; CL calls it kidney distal convoluted tubule epithelial cellTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Gene, MGI.