A new familial case of Jalili syndrome caused by a novel mutation in<i>CNNM4</i>

Topçu, Vehap; Yunus, Muhammed; Kedıcı, Cemile; Bakır, Abdullatif; Geylan, Dilay; Yılmazoğlu, Meltem Özgül

doi:10.3109/13816810.2016.1164192

Cited by 12 publications

(5 citation statements)

References 15 publications

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“…Yet, their key role in maintaining Mg 2+ homeostasis and their involvement in the development of Mg 2+ -related pathologies are undoubted. For example, mutations in CNNM2 or CNNM4 cause recessively inherited dominant hypomagnesemia and renal Mg 2+ wasting [2] or Jalili Syndrome, respectively [17][18][19][20][21][22][23]. Other disorders related to their altered activity include infertility [24,25], impaired brain development [26] along with neuropsychiatric disorders [27][28][29][30], and abnormal blood pressure levels [31].…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

Giménez-Mascarell

Oyenarte

González‐Recio

et al. 2019

IJMS

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The four member family of “Cyclin and Cystathionine β-synthase (CBS) domain divalent metal cation transport mediators”, CNNMs, are the least-studied mammalian magnesium transport mediators. CNNM4 is abundant in the brain and the intestinal tract, and its abnormal activity causes Jalili Syndrome. Recent findings show that suppression of CNNM4 in mice promotes malignant progression of intestinal polyps and is linked to infertility. The association of CNNM4 with phosphatases of the regenerating liver, PRLs, abrogates its Mg2+-efflux capacity, thus resulting in an increased intracellular Mg2+ concentration that favors tumor growth. Here we present the crystal structures of the two independent intracellular domains of human CNNM4, i.e., the Bateman module and the cyclic nucleotide binding-like domain (cNMP). We also derive a model structure for the full intracellular region in the absence and presence of MgATP and the oncogenic interacting partner, PRL-1. We find that only the Bateman module interacts with ATP and Mg2+, at non-overlapping sites facilitating their positive cooperativity. Furthermore, both domains dimerize autonomously, where the cNMP domain dimer forms a rigid cleft to restrict the Mg2+ induced sliding of the inserting CBS1 motives of the Bateman module, from a twisted to a flat disk shaped dimer.

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Section: Introductionmentioning

confidence: 99%

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

Giménez-Mascarell

Oyenarte

González‐Recio

et al. 2019

IJMS

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“…The CNBH domain does not interact with CBS-pair; nor does it interact with PRLs (18). One mutation in the domain has been linked to Jalili syndrome (21).…”

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confidence: 99%

The cyclic nucleotide–binding homology domain of the integral membrane protein CNNM mediates dimerization and is required for Mg2+ efflux activity

Chen

Kozlov

Fakih

et al. 2018

Journal of Biological Chemistry

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Proteins of the cyclin M family (CNNMs; also called ancient conserved domain proteins, or ACDPs) are represented by four integral membrane proteins that have been proposed to function as Mg 2؉ transporters. CNNMs are associated with a number of genetic diseases affecting ion movement and cancer via their association with highly oncogenic phosphatases of regenerating liver (PRLs). Structurally, CNNMs contain an N-terminal extracellular domain, a transmembrane domain (DUF21), and a large cytosolic region containing a cystathionine-␤synthase (CBS) domain and a putative cyclic nucleotidebinding homology (CNBH) domain. Although the CBS domain has been extensively characterized, little is known about the CNBH domain. Here, we determined the first crystal structures of the CNBH domains of CNNM2 and CNNM3 at 2.6 and 1.9 Å resolutions. Contrary to expectation, these domains did not bind cyclic nucleotides, but mediated dimerization both in crystals and in solution. Analytical ultracentrifugation experiments revealed an inverse correlation between the propensity of the CNBH domains to dimerize and the ability of CNNMs to mediate Mg 2؉ efflux. CNBH domains from active family members were observed as both dimers and monomers, whereas the inactive member, CNNM3, was observed only as a dimer. Mutational analysis revealed that the CNBH domain was required for Mg 2؉ efflux activity of CNNM4. This work provides a structural basis for understanding the function of CNNM proteins in Mg 2؉ transport and associated diseases.

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“…CNNM4 mutations have revealed clinical consequences which are limited to retinal function in CRD and bio‐mineralization of teeth in AI (Parry et al, ). Twenty‐four CNNM4 mutations, including a single base insertion, base pair duplication, missense changes, large deletions, and termination mutations have been characterized in patients suffering from JS around the world (Abu‐Safieh et al, ; Coppieters et al, ; Doucette et al, ; Huang et al, ; Jaouad et al, ; Kiessling, Mitter, Mitter, Langmann, & Müller, ; Lopez Torres, Schorderet, Schorderet, Valmaggia, & Todorova, ; Luder et al, ; Maia et al, ; Polok et al, ; Prasad et al, ; Rahimi‐Aliabadi et al, ; Topçu et al, ; Wang et al, ; Wawrocka et al, ; Zobor et al, ). These mutations presumably influence the divalent metal transporter function of CNNM4 protein.…”

Section: Discussionmentioning

confidence: 99%

A novel pathogenic missense variant in CNNM4 underlying Jalili syndrome: Insights from molecular dynamics simulations

Parveen

Mirza

Vanmeert

et al. 2019

Molec Gen & Gen Med

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Background Jalili syndrome (JS) is a rare cone‐rod dystrophy (CRD) associated with amelogenesis imperfecta (AI). The first clinical presentation of JS patients was published in 1988 by Jalili and Smith. Pathogenic mutations in the Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4 (CNNM4) magnesium transporter protein have been reported as the leading cause of this anomaly. Methods In the present study, a clinical and genetic investigation was performed in a consanguineous family of Pakistani origin, showing characteristic features of JS. Sanger sequencing was successfully used to identify the causative variant in CNNM4. Molecular dynamics (MD) simulations were performed to study the effect of amino acid change over CNNM4 protein. Results Sequence analysis of CNNM4 revealed a novel missense variant (c.1220G>T, p.Arg407Leu) in exon‐1 encoding cystathionine‐β‐synthase (CBS) domain. To comprehend the mutational consequences in the structure, the mutant p.Arg407Leu was modeled together with a previously reported variant (c.1484C>T, p.Thr495Ile) in the same domain. Additionally, docking analysis deciphered the binding mode of the adenosine triphosphate (ATP) cofactor. Furthermore, 60ns MD simulations were carried out on wild type (p.Arg407/p.Thr495) and mutants (p.Arg407Leu/p.Thr495Ile) to understand the structural and energetic changes in protein structure and its dynamic behavior. An evident conformational shift of ATP in the binding site was observed in simulated mutants disrupting the native ATP‐binding mode. Conclusion The novel identified variant in CNNM4 is the first report from the Pakistani population. Overall, the study is valuable and may give a novel insight into metal transport in visual function and biomineralization.

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A new familial case of Jalili syndrome caused by a novel mutation inCNNM4

Cited by 12 publications

References 15 publications

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

The cyclic nucleotide–binding homology domain of the integral membrane protein CNNM mediates dimerization and is required for Mg2+ efflux activity

A novel pathogenic missense variant in CNNM4 underlying Jalili syndrome: Insights from molecular dynamics simulations

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