LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.

Deletions within human chromosome 4p16.3 cause Wolf-Hirschhorn syndrome (WHS), which is characterized by severe mental and developmental defects. It is thought that haploinsufficiency of more than one gene contributes to the complex phenotype. We have cloned and characterized a novel gene (LETM1) that is deleted in nearly all WHS patients. LETM1 encodes a putative member of the EF-hand family of Ca(2+)-binding proteins. The protein contains two EF-hands, a transmembrane domain, a leucine zipper, and several coiled-coil domains. On the basis of its possible Ca(2+)-binding property and involvement in Ca(2+) signaling and/or homeostasis, we propose that haploinsufficiency of LETM1 may contribute to the neuromuscular features of WHS patients.

[1]  P. L. Bergsagel,et al.  The t(4;14) Translocation in Myeloma Dysregulates Both FGFR3 and a Novel Gene, MMSET, Resulting in IgH/MMSET Hybrid Transcripts , 1998 .

[2]  V. van Heyningen,et al.  Position effect in human genetic disease. , 1998, Human molecular genetics.

[3]  C. Mahaffey,et al.  The mouse stargazer gene encodes a neuronal Ca2+-channel γ subunit , 1998, Nature Genetics.

[4]  A. Moorman,et al.  WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. , 1998, Human molecular genetics.

[5]  R. Cannon,et al.  Pro-epileptic changes in synaptic function can be accompanied by pro-epileptic changes in neuronal excitability , 1998, Trends in Neurosciences.

[6]  A. Verkhratsky,et al.  Calcium and neuronal ageing , 1998, Trends in Neurosciences.

[7]  Shigeki Mitaku,et al.  SOSUI: classification and secondary structure prediction system for membrane proteins , 1998, Bioinform..

[8]  M. Rocchi,et al.  A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. , 1997, Blood.

[9]  B. Emanuel,et al.  Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders? , 1997, Human molecular genetics.

[10]  V. P. Johnson,et al.  Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs. , 1997, American journal of medical genetics.

[11]  A. Winterpacht,et al.  Human fibroblast growth factor receptor 3 gene (FGFR3): genomic sequence and primer set information for gene analysis , 1997, Human Genetics.

[12]  E. Schröck,et al.  Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3 , 1997, Nature Genetics.

[13]  M. Meisler,et al.  Mutation of the Ca2+ Channel β Subunit Gene Cchb4 Is Associated with Ataxia and Seizures in the Lethargic (lh) Mouse , 1997, Cell.

[14]  E. Zackai,et al.  A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. , 1997, Human molecular genetics.

[15]  A. Bairoch,et al.  The PROSITE database, its status in 1997 , 1997, Nucleic Acids Res..

[16]  C. Helms,et al.  Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly , 1996, Nature Genetics.

[17]  A. Winterpacht,et al.  Molecular cloning and chromosomal assignment of the human homologue of the rat cGMP-inhibited phosphodiesterase 1 (PDE3A)--a gene involved in fat metabolism located at 11p 15.1. , 1996, Genomics.

[18]  P. Scambler,et al.  Identification of a novel transcript disrupted by a balanced translocation associated with DiGeorge syndrome. , 1996, American journal of human genetics.

[19]  A. Winterpacht,et al.  Developmental expression of splicing variants of fibroblast growth factor receptor 3 (FGFR3) in mouse. , 1996, The International journal of developmental biology.

[20]  A. Winterpacht,et al.  Assignment of the human diacylglycerol kinase 4 (DAGK4) gene to chromosome 4p16.3. , 1996, Genomics.

[21]  Marco R. Celio,et al.  Guidebook to the calcium-binding proteins , 1996 .

[22]  B. Korf,et al.  Preliminary phenotypic map of chromosome 4p16 based on 4p deletions. , 1995, American journal of medical genetics.

[23]  R. King,et al.  Tyrosinase inhibition due to interaction of homocyst(e)ine with copper: the mechanism for reversible hypopigmentation in homocystinuria due to cystathionine beta-synthase deficiency. , 1995, American journal of human genetics.

[24]  N. Tommerup,et al.  Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9 , 1994, Cell.

[25]  Sahar Mansour,et al.  Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene , 1994, Nature.

[26]  H. Kawasaki,et al.  Calcium-binding proteins. 1: EF-hands. , 1994, Protein profile.

[27]  D. Church,et al.  Isolation of genes from complex sources of mammalian genomic DNA using exon amplification , 1994, Nature Genetics.

[28]  C. Amemiya,et al.  A new bacteriophage P1–derived vector for the propagation of large human DNA fragments , 1994, Nature Genetics.

[29]  F. Collins,et al.  A cosmid contig and high resolution restriction map of the 2 megabase region containing the Huntington's disease gene , 1993, Nature Genetics.

[30]  Kay Hofmann,et al.  Tmbase-A database of membrane spanning protein segments , 1993 .

[31]  M. Meyn,et al.  Molecular definition of the smallest region of deletion overlap in the Wolf-Hirschhorn syndrome. , 1992, American journal of human genetics.

[32]  C. Heizmann,et al.  Changes in Ca2+-binding proteins in human neurodegenerative disorders , 1992, Trends in Neurosciences.

[33]  J. Burn,et al.  A submicroscopic translocation, t(4;10), responsible for recurrent Wolf-Hirschhorn syndrome identified by allele loss and fluorescent in situ hybridisation. , 1992, Journal of medical genetics.

[34]  A. Lupas,et al.  Predicting coiled coils from protein sequences , 1991, Science.

[35]  P. Sharp,et al.  Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Charles R.scriver,et al.  The Metabolic basis of inherited disease , 1989 .

[37]  G. Church,et al.  Genomic sequencing. , 1993, Methods in molecular biology.

[38]  V. P. Johnson,et al.  The Wolf‐Hirschhorn (4p‐) syndrome , 1976, Clinical genetics.

[39]  U. Wolf,et al.  [Deficiency on the short arms of a chromosome No. 4]. , 1965, Humangenetik.