# Novel CNNM2 variant causing hypomagnesemia and early-onset calcium pyrophosphate deposition disease: A case report

Caroline Robert, Léa Perrot, Alexia Zelus, Emmanuel Letavernier, Guillaume Courbon, Pierre Lafforgue, Thomas Robert, Nathalie Balandraud

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## ► To cite this version:

Caroline Robert, Léa Perrot, Alexia Zelus, Emmanuel Letavernier, Guillaume Courbon, et al., Novel CNNM2 variant causing hypomagnesemia and early-onset calcium pyrophosphate deposition disease: A case report. Joint Bone Spine, 2026, 93 (1), pp.105982. 10.1016/j.jbspin.2025.105982. hal-05501534

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Case report

# Novel CNNM2 variant causing hypomagnesemia and early-onset calcium pyrophosphate deposition disease: A case report

Caroline Robert<sup>a,1</sup>, Léa Perrot<sup>a,1</sup>, Alexia Zelus<sup>b</sup>, Emmanuel Letavernier<sup>c,d,e</sup>, Guillaume Courbon<sup>f</sup>, Pierre Lafforgue<sup>a</sup>, Thomas Robert<sup>g,h</sup>, Nathalie Balandraud<sup>a,i,*</sup>

<figure><img src="image_5.png" /></figure>

## ARTICLE INFO

**Article history:**

Accepted 22 September 2025

Available online 27 September 2025

**Keywords:**

Calcium pyrophosphate deposition

Chondrocalcinosis

CNNM2 mutation

CPPD

Hypomagnesemia

## ABSTRACT

Calcium pyrophosphate deposition (CPPD) disease is a common crystal arthropathy in the elderly, but its early-onset forms are rare. While secondary hypomagnesemia is a recognized contributor to CCPD, inherited renal magnesium-wasting syndromes remain underdiagnosed. Here we performed a whole exome sequencing (ES) in order to detect pathogenic variants in a 58-year-old male patient with early and severe, refractory CPPD disease. We conducted a comprehensive clinical, biochemical, radiological, and genetic evaluation of the patient. ES was performed and filtered for rare, likely pathogenic variants following ACMG/AMP criteria. Cascade genetic testing was performed in family members. Hypomagnesemia with inappropriate renal magnesium loss was found. Radiographs revealed diffuse chondrocalcinosis ES identified a novel heterozygous Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM2) missense variant (c.319G>C; p.Gly107Arg), absent from population databases and predicted deleterious (REVEL 0.82). This variant affects a highly conserved residue in the extracellular β-barrel domain. Family screening revealed two additional carriers with isolated hypomagnesemia, consistent with autosomal dominant inheritance. CNNM2 encodes a basolateral magnesium transporter in the tubule. This is the first reported case of CPPD linked to a CNNM2 variant through persistent hypomagnesemia. Its variants have been linked to renal hypomagnesemia, neurological comorbidities, but no link to CPPD has been described. This expands the phenotypic spectrum of CNNM2-related disorders and highlights the relevance of genetic testing in CPPD cases with unexplained hypomagnesemia. Building on published functional studies and domain-level protein modeling, we propose a simplified three-tier classification scheme that organizes CNNM2 variants into clinically meaningful categories.

© 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Société Française de Rhumatologie. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

## 1. Introduction

Calcium pyrophosphate deposition (CPPD) disease is a microcrystalline arthropathy affecting approximately 4% to 7% of the adult population in Europe and the United States and its prevalence

increases significantly with age [1]. Well-established risk factors include local joint trauma (e.g., meniscectomy), and metabolic conditions such as hyperparathyroidism, haemochromatosis, hypophosphatasia, and hypomagnesemia.

In young individuals, severe inherited forms of CPPD have been reported to mutations in genes such as ANKH and TNFRSF11B. Calcium pyrophosphate crystals (CPP) formation is promoted by excess extracellular pyrophosphate (PPi), and magnesium deficiency contributes by impairing PPi degradation.

Although secondary hypomagnesemia is a known metabolic contributor to CPPD, its role as a primary inherited cause remains

<footnote><sup>a</sup> Rheumatology Department, Sainte-Marguerite Hospital, Aix-Marseille University, AP-HM, 13009 Marseille, France</footnote>

<footnote><sup>b</sup> Eurofins Biomnis, Département génétique et séquençage, 69007 Lyon, France</footnote>

<footnote><sup>c</sup> AP-HP, Hôpital Tenon, service des explorations fonctionnelles multidisciplinaires, 75020 Paris, France</footnote>

<footnote><sup>d</sup> Inserm UMR S 1155, Hôpital Tenon, 75020 Paris, France</footnote>

<footnote><sup>e</sup> Sorbonne Université, UFR de médecine, 75020 Paris, France</footnote>

<footnote><sup>f</sup> Inserm U1059, SAINBIOSE, university of Saint-Étienne, Mines, 4200 Saint-Étienne, France</footnote>

<footnote><sup>g</sup> Département de néphrologie et de néphrogénomique, Hôpital Saint-Joseph, 13008 Marseille, France</footnote>

<footnote><sup>h</sup> Aix-Marseille Université, Inserm, INRAE, C2VN, 13005 Marseille, France</footnote>

<footnote><sup>i</sup> ARTHEMIS (ARTHrites Microchimerism and Inflammations), Inserm UMRs 1097, Aix-Marseille University, 13009 Marseille, France</footnote>

<footnote>* Corresponding author at: Rheumatology Department, Sainte-Marguerite Hospital, Aix-Marseille University, AP-HM, 13009 Marseille, France.
E-mail address: nathalie.balandraud@ap-hm.fr (N. Balandraud).</footnote>

<footnote n="1">¹ These two authors have equally contributed to this work.</footnote>
under-recognized. A few types of genetic hypomagnesemia (e.g., Gitelman syndrome) have been associated with CPPD disease [2].

We report here the first case of early-onset, refractory CPPD disease secondary to a novel heterozygous *Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM2)* variant [3]. This previously unreported mutation suggests a new genetic cause of CPPD. *CNNM2* (located at 10q24.32-33) encodes a magnesium transporter expressed in the distal convoluted tubule cells of the kidney. It plays a key role in active magnesium reabsorption and the maintenance of systemic magnesium homeostasis. To date, no link has been reported between *CNNM2* variants and musculoskeletal manifestations.

# 2. Observation

## 2.1. Clinical presentation

A 58-year-old white European man was referred to the rheumatology department in Marseille for evaluation and management of severe, early-onset CPPD disease. The first episode of joint inflammation occurred at the age of 19 years and affected both knees. Over the years, the disease progressed to involve multiple joints, including the wrists, elbows, shoulders, ankles, and feet. Despite treatment with colchicine and non-steroidal anti-inflammatory drugs (NSAIDs), the disease remained active, with frequent flares that significantly impaired mobility. The patient required walking aids during flares and exhibited upper limb weakness, joint stiffness, and multiple joint deformities. The patient is also affected by early-onset bilateral deafness and a mild overweight condition (body mass index: 26.7). His medical history includes appendectomy, tonsillectomy, bilateral meniscal surgeries, arthroscopic joint lavages, and a left wrist fracture. There is no personal or family history of autoimmune or inflammatory diseases (such as psoriasis, inflammatory bowel disease [IBD], uveitis, or aphthous stomatitis), and no self-reported alcohol or tobacco use. The patient had no cardiovascular or metabolic comorbidities and had worked as an automobile mechanic before becoming occupationally disabled.

Clinical examination revealed bilateral elbow flexion contracture, right knee effusion, and significant right wrist stiffness, with no extra-articular manifestations observed. From age 56, the patient developed upper extremity muscle weakness that has limited hand function.

## 2.2. Laboratory findings

Hemogram, glycaemia and renal function were normal, and inflammatory markers were within reference ranges. However, persistent hypomagnesemia was identified, with a serum magnesium concentration of 0.62 mmol/L (normal: 0.66-1.07 mmol/L), and reduced intra-erythrocytic magnesium of 1.43 mmol/L (normal: 1.65-2.5). The baseline urinary FeMg was 2.88%, already inappropriately elevated in the context of hypomagnesemia (with a 2% threshold in this context).

A full immunological workup was negative, including rheumatoid factor, anti-cyclic citrullinated peptide antibodies, anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, and HLA-B27 typing.

Synovial fluid was aspirated from the knee and analyzed using compensated polarised light microscopy. The presence of rhomboid-shaped crystals that exhibit weakly positive birefringence was consistent with the diagnosis of CPPD.

## 2.3. Radiographic findings

X-rays were performed at the time of diagnosis (Fig. 1). Radiographs of the hands revealed bilateral calcification of the triangular

fibrocartilage at the wrists. Typical chondrocalcinosis was found in the knees, shoulders, and elbows.

## 2.4. Evolution

No common secondary causes of hypomagnesemia, such as gastrointestinal losses, diuretic use, proton pump inhibitors, or diabetes, were identified [4]. In light of the patient's unusually early disease onset, lack of metabolic or inflammatory aetiologies, and persistent renal magnesium loss, a genetic origin was suspected.

Following oral supplementation with 600 mg/day of magnesium hydroxide [Mg(OH)₂] and magnesium chloride [MgCl₂], the patient's serum magnesium increased modestly to 0.72 mmol/L but remained subnormal. Concomitantly, FeMg increased to 4.1%, further supporting the diagnosis of renal magnesium wasting, unmasked by the magnesium challenge. Serum creatinine remained stable from 90 to 92 µmol/L, and urea was initially at 1.43 mmol/L with no data provided post-supplementation. Total calcium decreased from 2.56 to 2.44 mmol/L, while ionized calcium decreased slightly from 1.23 to 1.21 mmol/L. Phosphorus increased from 0.87 to 0.89 mmol/L, and parathyroid hormone (PTH) increased significantly from 55.4 to 85.8 pg/mL. 25 OH Vitamin D was initially at 66.2 nmol/L, and 1,25 OH Vitamin D was at 59.9 pmol/L, with no post-supplementation data provided for either. Alkaline phosphatase (ALP) was stable from 65 to 66 U/L, and bone-specific alkaline phosphatase (BALP) decreased from 12.7 to 11.4 µg/L. Ferritin data was not provided post-supplementation, with a baseline of 51.4 µg/L, and thyroid stimulating hormone (TSH) decreased slightly from 0.56 to 0.54 mU/mL. Urine parameters from a 24-hour collection showed that diuresis increased from 0.8 to 1 L, Sodium decreased from 225 to 167 mmol/L, calcium decreased from 5.3 to 3.48 mmol/L, chloride decreased from 238 to 105 mmol/L, and phosphorus decreased from 25.9 to 18.5 mmol/L.

## 2.5. Genetic investigation

Genomic DNA was extracted from peripheral blood using the QIAsymphony® DSP DNA Mini Kit (QIAGEN, Germany) on the QIAsymphony platform, following the manufacturer's protocol. From 50 ng of fragmented DNA, indexed libraries were prepared and hybridised with biotinylated probes from the Twist Human Comprehensive Exome kit (37 Mb). Exome sequencing (ES) was performed with the Illumina NextSeq 2000 platform (2 × 150 bp) using FlowCell P3. ES identified a de novo heterozygous mis-sense variant in *CNNM2* (NM_017649.5:c.319G>C; p.Gly107Arg). This variant was absent from gnomAD v4 and was predicted to be deleterious (REVEL score: 0.82, Z-score: 5.02), affecting a highly conserved region within the extracellular β-barrel domain. The Glycine 107 residue belongs to a beta-sheet of the extracellular β-barrel domain and forms a strongly predicted hydrogen bond with the next strand in the beta-sheet, Threonine 169. Using the Alpha-Fold configuration (Q9H8M5) in ChimeraX [5], a backbone-to-backbone N-H...O bond is predicted, in which the NH group from G107 donates a hydrogen atom to the CO group from T169. This liaison would be nearly linear, strong, and geometrically favorable (donor-acceptor distance: 3.023Å; hydrogen-acceptor distance: 2.049Å; angle: 161.3°). Conversely, substitution p.G107R would alter geometry, steric hindrance, and electrostatic balance in the beta-sheet and possibly disrupt the extracellular β-barrel domain and its abilities, namely (i) to transport Mg2+, (ii) to bind ATP-Mg2+ complexes, and (iii) to interact with other proteins and regulatory molecules (Fig. 2).

No additional pathogenic variants were identified in other genes known to be associated with CPPD or renal tubulopathies.
<figure><img src="image_6.png" /><figcaption>**Fig. 1.** Clinical and radiological features of early-onset calcium pyrophosphate deposition disease (CPPD) associated with a *Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM2)* variant. A. Elbow. B. Left shoulder. C. Lateral knee. D. Frontal right knee. E. Frontal left knee. F. Right wrist. G. Left wrist.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 2.** Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM2) predicted 3D structure, with a hydrogen bond between Gly107 and Thr169 (backbone-to-backbone N-H···O) nearly linear, strong, and geometrically favorable (donor-acceptor distance: 3.023Å; hydrogen-acceptor distance: 2.049Å; angle: 161.3°).</figcaption></figure>

## 2.6. Family evaluation and pedigree

Cascade screening of the patient's three children revealed that two were heterozygous carriers of the CNNM2 variant. His 22-year-old daughter had asymptomatic hypomagnesemia (serum magnesium: 0.57 mmol/L), while his 30-year-old son showed mild symptoms (muscle cramps) with a magnesium serum level of 0.63 mmol/L. The third child, a 23-year-old daughter who did not carry the mutation, had normal serum magnesium of 0.90 mmol/L. Interestingly, the patient's wife retrospectively reported that, during her pregnancy with her son, she experienced recurrent symptomatic hypomagnesemia requiring intravenous magnesium supplementation. This raises the hypothesis that foetal renal magnesium wasting may influence maternal magnesium homeostasis via the placental circulation, although this

mechanism remains speculative and would warrant further investigation.

## 3. Discussion

We report a unique, previously unknown case of CPPD disease secondary to hypomagnesemia associated with a novel heterozygous missense variant in CNNM2 (p.Gly107Arg). This gene encodes Cyclin M2, a basolateral magnesium transporter predominantly expressed in the distal convoluted tubule of the kidney. CNNM2 plays a key role in active magnesium reabsorption and the maintenance of systemic magnesium homeostasis [6].

Magnesium (Mg) is the eleventh most abundant element by mass in the human body and is essential to all cells and some 300 enzymes. Mg²⁺ ions interact with polyphosphate compounds
<caption>**Table 1**</caption>

Simplified classification of CNNM2 variants. Variants are grouped into three classes based on their molecular mechanism, affected domain, and clinical phenotype.

<table><thead><tr><th>Class</th><th>Mechanism</th><th>Variant type</th><th>Domain</th><th>Clinical phenotype</th><th>Mg<sup>2+</sup> uptake (% WT)</th><th>Examples</th><th>References</th></tr></thead><tbody><tr><td>I</td><td>Complete or near-complete loss of function</td><td>Nonsense, frameshift, deletions</td><td>CNBH</td><td>HSMR: seizures, ID, brain anomalies, severe hypomagnesemia</td><td>~10-20%</td><td>p.Tyr314*, p.Ser795*, del exons 3-8</td><td>[8,13]</td></tr><tr><td>II</td><td>Severe structural disruption</td><td>Missense</td><td>DUF21</td><td>Atypical HSMR: ID ± seizures, moderate hypomagnesemia</td><td>~7-18%</td><td>p.V324L, p.Leu418Pro, p.G437E</td><td>[8,10]</td></tr><tr><td>III</td><td>Partial loss of function</td><td>Missense</td><td>DUF21, β-barrel (extracellular)</td><td>Isolated hypomagnesemia ± ADHD, CPPD, or mild extra-renal features</td><td>~38-58%</td><td>p.D335N, p.M383V, p.Ala92Pro, p.Gly107Arg</td><td>[8, current case]</td></tr></tbody></table>

ADHD: attention deficit hyperactivity disorder; CNBH: cyclic nucleotide-binding homology domain; CPPD: calcium pyrophosphate deposition disease; DUF21: domain of unknown function 21 (transmembrane region with 4 helices); HSMR: hypomagnesemia, seizures, and mental retardation syndrome; ID: intellectual disability.

such as ATP, DNA and RNA. Regarding osteoarticular disorder, it has direct effects on osteoblast functions with regulation of Runx2 (runt related transcription factor 2), BMP2 (bone morphogenetic protein2), OPN (Osteopontin) COL1 (type I collagen), and Wnt/b-catenin pathway [7]. It also plays an essential role in extracellular PPI metabolism. A reduction in magnesium levels leads to decreased activity of TNAP (tissue non specific alkaline phosphatase), impairing PPI hydrolysis and thereby favoring CPP crystal formation. While hypomagnesemia is a recognized contributor to CPPD, very few cases have directly implicated genetic renal magnesium-wasting disorders as causative factors.

The CNNM2 protein comprises several structural domains reflecting its dual function in renal magnesium transport and intracellular signalling. It includes an N-terminal extracellular domain (residues ~1-130) harbouring a glycosylation site at asparagine 112 (N112), a transmembrane DUF21 domain (residues ~250-450) containing four α-helices (TM1-TM4), and a cytosolic region composed of the CBS-pair regulatory domains ([Bateman domain, ~550-650] and the CNBH domain [~650-820]).

The p.Gly107Arg variant identified in our patient is not found in population reference databases (gnomAD v4), is predicted to be deleterious (REVEL score: 0.82), and affects a highly conserved residue located within the β4 strand of the CNNM2 extracellular β-barrel domain. Although this region is spatially distant from the DUF21 and the cytosolic CBS domains, CNNM2 functions as an integrated allosteric system. Structural studies of CNNM-family orthologues (e.g., CorC) suggest that conformational changes initiated in the extracellular domain may be transmitted through the transmembrane region via a connector helix (H0) to the intracellular CBS module [8].

The phenotypic spectrum of CNNM2-related disorders is highly dependent on the nature and zygosity of the underlying genetic variant. Biallelic loss-of-function mutations in CNNM2 typically lead to a syndromic phenotype characterized by severe hypomagnesemia, early-onset seizures, and intellectual disability, known as hypomagnesemia, seizures, and mental retardation (HSMR) syndrome (OMIM 616418). In contrast, heterozygous variants – especially those located in peripheral or structurally modulatory domains such as the β-barrel – are associated with isolated renal magnesium wasting and moderate hypomagnesemia (OMIM 613882), often asymptomatic or with mild clinical expression [9,10]. However, the gene was identified to be a robust schizophrenia risk gene, and was highly expressed in human neurons according to single cell RNA-seq data [11].

Functional studies of pathogenic variants have shown that mutations in the CBS or DUF21 domains, which are critical for magnesium sensing and transport, tend to result in more severe phenotypes, while variants in the extracellular domain (such as p.Gly107Arg) may cause partial loss of function, leading to milder biochemical and clinical presentations. In this context, the substitu-

tion of glycine by arginine at position 107 may disrupt local β-barrel folding and compromise structural communication with DUF21. Indeed, Glycine is small non-polar and electrically neutral while Arginine is larger, strongly basic and positively charged, may be causing not only steric hindrance and conformation change but also disrupting electrostatics required for divalent metal binding. This could impair the protein's ability to adopt conformations required for magnesium transport, leading to a partial loss of function. This model is supported by the patient's moderate but persistent hypomagnesemia, which is less severe than that typically seen in biallelic mutations affecting the CBS or DUF21 domains, and by the absence of neurological features or intellectual disability [8].

These observations underscore a dosage-sensitive effect of CNNM2 function, where the location and biophysical impact of each variant modulate the degree of magnesium transport impairment and the associated clinical phenotype. The growing number of reported CNNM2 variants and the expanding phenotypic spectrum – from isolated renal magnesium wasting to complex neurodevelopmental syndromes – highlight the urgent need for a structured, mechanistically informed classification. Building on published functional studies and domain-level protein modelling, we propose a simplified three-tier classification scheme that organizes CNNM2 variants into clinically meaningful categories (Table 1).

This case broadens the phenotypic and functional spectrum of CNNM2-related disorders. It highlights the importance of considering monogenic causes of magnesium imbalance in patients with early and severe CPPD, particularly when standard metabolic, inflammatory, and drug-related causes have been excluded. In such contexts, genetic testing can provide crucial insights for diagnosis and management.

Magnesium uptake is estimated from published functional studies [12,13]. Magnesium uptake values are derived from in vitro 25 mg uptake assays performed in HEK293 cells and represent average residual activity relative to wild-type protein.

Class I variants represent complete or near-complete loss of function, typically due to nonsense mutations or large deletions affecting the CNBH domain or broader coding regions. These variants are strongly associated with the full clinical spectrum of CNNM2-related HSMR syndrome, including profound hypomagnesemia, intellectual disability, early-onset epilepsy, and brain malformations. Class II comprises missense variants that cause major structural disruption, particularly within the DUF21 transmembrane domain. These mutations tend to result in moderate impairment of magnesium transport and are commonly associated with atypical HSMR presentations, characterised by isolated or partial neurocognitive features and intermediate hypomagnesemia. Class III includes hypomorphic missense variants that preserve partial function and localise to regulatory or extracellular regions, such as the β-barrel domain or peripheral segments of DUF21. These are most often associated with isolated renal magnesium loss and
may present without overt neurological involvement. Notably, the present case, which harbours a de novo p.Gly107Arg variant in the β-barrel domain, is, to our knowledge, the first to associate CNNM2 dysfunction with CPPD disease, thereby extending the phenotypic relevance of Class III variants to crystal-related arthropathies.

## Founding

Laboratory tests and genetic analysis were found by French health insurance.

## Ethics

Written informed consent was obtained from the patient for genetic testing and the publication of anonymized clinical information, including imaging data. This case report was declared the ethics committee to the Assistance publique-Hôpitaux de Marseille.

## Disclosure of interest

The authors declare that they have no competing interest.

## Acknowledgments

Acknowledgments to Dr. Olivier Muis-Pistor who provided patient medical history for 30 years.

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