First report of a short in‐frame biallelic deletion removing part of the EGF‐like domain calcium‐binding motif in LTBP4 and causing autosomal recessive cutis laxa type 1C

Cutis laxa (CL) is a rare connective tissue disorder characterized by wrinkled, abundant and sagging skin, sometimes associated with systemic impairment. Biallelic alterations in latent transforming growth factor beta‐binding protein 4 gene (LTBP4) cause autosomal recessive type 1C cutis laxa (ARCL1C, MIM #613177). The present report describes the case of a 17‐months‐old girl with cutis laxa together with a literature review of previous ARCL1C cases. Based on proband main clinical signs (cutis laxa and pulmonary emphysema), clinical exome sequencing (CES) was performed and showed a new nine base‐pairs homozygous in‐frame deletion in LTBP4 gene. RT‐PCR and cDNA Sanger sequencing were performed in order to clarify its impact on RNA. This report demonstrates that a genetic alteration in the EGF‐like 14 domain calcium‐binding motif of LTBP4 gene is likely responsible for cutis laxa in our patient.

[1]  Min Zhang,et al.  Cysteine Substitution and Calcium-Binding Mutations in FBN1 cbEGF-Like Domains Are Associated With Severe Ocular Involvement in Patients With Congenital Ectopia Lentis , 2022, Frontiers in Cell and Developmental Biology.

[2]  F. Alkuraya,et al.  Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome. , 2021, American journal of human genetics.

[3]  Oriol Vinyals,et al.  Highly accurate protein structure prediction with AlphaFold , 2021, Nature.

[4]  J. Traeger-Synodinos,et al.  Phenotype‐driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders , 2021, American journal of medical genetics. Part A.

[5]  F. Alkuraya,et al.  Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome. , 2021, American journal of human genetics.

[6]  B. Callewaert,et al.  Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis. , 2021, Advances in experimental medicine and biology.

[7]  Z. Qin,et al.  Two novel compound heterozygous variants of LTBP4 in a Chinese infant with cutis laxa type IC and a review of the related literature , 2020, BMC Medical Genomics.

[8]  M. Kabra,et al.  Identification of a Novel 19-bp Deletion Mutation in LTBP4 Using Exome Sequencing in Two Siblings with Autosomal Recessive Cutis Laxa Type 1C , 2019, Journal of Pediatric Genetics.

[9]  M. Ritelli,et al.  Clinical and molecular characterization of an 18‐month‐old infant with autosomal recessive cutis laxa type 1C due to a novel LTBP4 pathogenic variant, and literature review , 2019, Molecular genetics & genomic medicine.

[10]  A. Hoischen,et al.  Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa. , 2017, American Journal of Human Genetics.

[11]  B. Callewaert,et al.  LTBP4-Related Cutis Laxa , 2016 .

[12]  J. Ganesh,et al.  Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa. , 2015, American journal of human genetics.

[13]  Jenq-Wen Huang,et al.  Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability. , 2015, Human molecular genetics.

[14]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[15]  D. Rifkin,et al.  Function of Latent TGFβ Binding Protein 4 and Fibulin 5 in Elastogenesis and Lung Development , 2015, Journal of cellular physiology.

[16]  S. Mundlos,et al.  Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1. , 2014, Molecular genetics and metabolism.

[17]  K. Heimdal,et al.  Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa , 2013, Human Mutation.

[18]  D. Lin,et al.  Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome , 2011, American journal of medical genetics. Part A.

[19]  R. Mecham,et al.  New insights into the pathogenesis of autosomal‐dominant cutis laxa with report of five ELN mutations , 2011, Human mutation.

[20]  K. Holland,et al.  Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. , 2009, American journal of human genetics.

[21]  J. Hoyer,et al.  Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin‐4 gene mutation , 2009, Clinical genetics.

[22]  M. Dubé,et al.  Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2. , 2009, American journal of human genetics.

[23]  Ron A Wevers,et al.  Autosomal recessive cutis laxa syndrome revisited , 2009, European Journal of Human Genetics.

[24]  S. Robertson,et al.  Functional copper transport explains neurologic sparing in Occipital Horn syndrome , 2006, Genetics in Medicine.

[25]  Kevan G Lewis,et al.  Acquired disorders of elastic tissue: Part II. decreased elastic tissue. , 2004, Journal of the American Academy of Dermatology.

[26]  J. Lambert,et al.  Cutis laxa of the autosomal recessive type in a consanguineous family. , 2003, European journal of dermatology : EJD.

[27]  R. Timpl,et al.  Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene. , 2003, American journal of human genetics.

[28]  I. Kaitila,et al.  Ten novel FBN2 mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype , 2002, Human mutation.

[29]  P. Handford,et al.  Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context. , 2000, Human molecular genetics.

[30]  I. Campbell,et al.  Solution Structure of a Pair of Calcium-Binding Epidermal Growth Factor-like Domains: Implications for the Marfan Syndrome and Other Genetic Disorders , 1996, Cell.

[31]  P. Handford,et al.  Calcium binding properties of an epidermal growth factor-like domain pair from human fibrillin-1. , 1996, Journal of molecular biology.

[32]  P. Handford,et al.  The structure of a Ca2+-binding epidermal growth factor-like domain: Its role in protein-protein interactions , 1995, Cell.

[33]  D. Stuart,et al.  The structure of a Ca(2+)-binding epidermal growth factor-like domain: its role in protein-protein interactions. , 1995, Cell.

[34]  C. Kielty,et al.  The role of calcium in the organization of fibrillin microfibrils , 1993, FEBS letters.

[35]  M. Ullner,et al.  How an epidermal growth factor (EGF)-like domain binds calcium. High resolution NMR structure of the calcium form of the NH2-terminal EGF-like domain in coagulation factor X. , 1994, The Journal of biological chemistry.

[36]  I. D. Campbell,et al.  Key residues involved in calcium-binding motifs in EGF-like domains , 1991, Nature.

[37]  Tian Xu,et al.  Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila , 1990, Cell.

[38]  S. Cohen,et al.  Epidermal growth factor , 1972, The Journal of investigative dermatology.