Report of two unrelated families with Jalili syndrome and a novel nonsense heterozygous mutation in  CNNM4  gene

Maia, Célia Márcia Fernandes; Machado, Renato Assis; Gil-da-Silva-Lopes, Vera Lúcia; Lustosa-Mendes, Elaine; Rim, Priscila Hae Hyun; Dias, Verônica Oliveira; Martelli, Daniella Reis Barbosa; Nasser, Luciano Sólia; Coletta, Ricardo D.; Martelli‐Júnior, Hercílio

doi:10.1016/j.ejmg.2018.02.003

Cited by 8 publications

(7 citation statements)

References 18 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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“…Jalili syndrome (JS) (OMIM # 217080), first described by Jalili and Smith in 1988 in a large Arab consanguineous family in Gaza strip, is a rare autosomal‐recessive inherited disease (Jalili & Smith, 1988 ). It has also been reported in Moroccan, Iranian, Polish, Kosovan, American, Turkish, Scotland, Lebanon, Guatemalan, Brazilian, Indian, and Chinese populations (Maia et al, 2018 ; Parry et al, 2009 ; Polok et al, 2009 ; Prasov et al, 2020 ; Purwar et al, 2015 ; Wang et al, 2015 ; Xu et al, 2015 ). The characteristic features of Jalili syndrome are Cone‐rod dystrophy (CRD) and amelogenesis imperfecta(AI) (Daneshmandpour et al, 2019 ).…”

Section: Introductionmentioning

confidence: 80%

“…So far, Jalili syndrome has been reported in approximately 34 families around the world, among which only one case was with Chinese ethnicity (Maia et al, 2018 ; Prasov et al, 2020 ; Wang et al, 2015 ). In the present study, we described the detailed clinical manifestations of a Chinese family with Jalili syndrome and investigated the underlying genetic defect.…”

Section: Introductionmentioning

confidence: 99%

Novel homozygous nonsynonymous variant of CNNM4 gene in a Chinese family with Jalili syndrome

Yan-feng

et al. 2022

Molec Gen & Gen Med

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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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Report of two unrelated families with Jalili syndrome and a novel nonsense heterozygous mutation in CNNM4 gene

Cited by 8 publications

References 18 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

Novel homozygous nonsynonymous variant of CNNM4 gene in a Chinese family with Jalili syndrome

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

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