A novel frame-shift mutation of GLI3 causes non-syndromic and complex digital anomalies in a Chinese family.

A three-generation Han Chinese family was found with complex digital anomalies including various types of polydactyly and syndactyly of fingers and toes. Some extra digits are composed only of soft tissues while others are complete fingers or toes, making this complex case different from previously reported pedigrees. The digital disease shows an autosomal dominant inheritance model. To locate the causative gene, whole-genome SNP analysis was performed using Illumina 370 K CNV-Quad chips followed by linkage analysis with a self-developed algorithm Haplo2Ped (http://bighapmap.big.ac.cn/software.html). Three candidate regions with the highest signals (LOD scores 2.1070) were identified. In one region from 33,904,914 bp to 45,529,271 bp in chromosome 7, GLI3 was selected for further analysis. PCR sequencing and subsequent clone sequencing revealed a single nucleotide deletion (c.2884delG) in exon 14. This frame shift mutation generated a truncated protein with 40 non-endogenous amino acids in its C-terminal (p.Asp962MetfsX41). GLI3 was previously reported to associate with Greig Cephalopolysyndactyly Syndrome, Pallister-Hall Syndrome, and a few cases of preaxial and postaxial polydactylies. We report for the first time a novel mutation of GLI3 causing various digital abnormalities, including multi symptoms as both polydactyly and syndactyly among affected members but no other body maldevelopments (non-syndromic).

[1]  S. Cichon,et al.  Localization of a gene for syndactyly type 1 to chromosome 2q34-q36. , 2000, American journal of human genetics.

[2]  A. McMahon,et al.  Cholesterol Modification of Sonic Hedgehog Is Required for Long-Range Signaling Activity and Effective Modulation of Signaling by Ptc1 , 2001, Cell.

[3]  D. Donnai,et al.  De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models , 2002, Journal of medical genetics.

[4]  J. Korving,et al.  Function and regulation of Alx4 in limb development: complex genetic interactions with Gli3 and Shh. , 2005, Developmental biology.

[5]  C. Tickle,et al.  A model for anteroposterior patterning of the vertebrate limb based on sequential long- and short-range Shh signalling and Bmp signalling. , 2000, Development.

[6]  V. McKusick,et al.  The genetics of hand malformations. , 1978, Birth defects original article series.

[7]  S. Nelson,et al.  Ciliary abnormalities due to defects in the retrograde transport protein DYNC2H1 in short-rib polydactyly syndrome. , 2009, American journal of human genetics.

[8]  Philip A Beachy,et al.  Hedgehog-Regulated Processing of Gli3 Produces an Anterior/Posterior Repressor Gradient in the Developing Vertebrate Limb , 2000, Cell.

[9]  G. Gillessen‐kaesbach,et al.  Bilateral complete polysyndactyly (type IV Haas). , 1991, American journal of medical genetics.

[10]  W. Blauth,et al.  Classification of polydactyly of the hands and fee , 2004, Archives of orthopaedic and traumatic surgery.

[11]  S. O’Brien,et al.  The GLI-Kruppel family of human genes , 1988, Molecular and cellular biology.

[12]  T. Kornberg,et al.  Proteolysis That Is Inhibited by Hedgehog Targets Cubitus interruptus Protein to the Nucleus and Converts It to a Repressor , 1997, Cell.

[13]  K. Grzeschik,et al.  GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families , 1991, Nature.

[14]  R. Winter,et al.  Localization of a gene for oculodentodigital syndrome to human chromosome 6q22-q24. , 1997, Human molecular genetics.

[15]  M. Kalff-Suske,et al.  Boy with syndactylies, macrocephaly, and severe skeletal dysplasia: not a new syndrome, but two dominant mutations (GLI3 E543X and COL2A1 G973R) in the same individual. , 2000, American journal of medical genetics.

[16]  L. Biesecker,et al.  GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  G. Sorge,et al.  Autosomal recessive postaxial polydactyly type A in a Sicilian family. , 1978, Journal of medical genetics.

[18]  U. C. Patel,et al.  The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. , 1999, American journal of human genetics.

[19]  J. Seidman,et al.  A complex bilateral polysyndactyly disease locus maps to chromosome 7q36 , 1994, Nature Genetics.

[20]  E. Jabs,et al.  Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome. , 2007, American journal of human genetics.

[21]  W. V. D. Van de Ven,et al.  The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly , 2002, Journal of medical genetics.

[22]  R. Kobayashi,et al.  Hedgehog Elicits Signal Transduction by Means of a Large Complex Containing the Kinesin-Related Protein Costal2 , 1997, Cell.

[23]  R Rizzo,et al.  Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. , 1999, Human molecular genetics.

[24]  K. Kinzler,et al.  GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity , 1990, Molecular and cellular biology.

[25]  K. Grzeschik,et al.  The spectrum of hand and foot malformations in patients with Greig cephalopolysyndactyly , 2007, Journal of children's orthopaedics.

[26]  Yina Li,et al.  Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity , 2002, Nature.

[27]  U. C. Patel,et al.  Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis. , 1997, American journal of human genetics.

[28]  S. Temtamy,et al.  Brachydactyly , 2008, Orphanet journal of rare diseases.

[29]  S. Mundlos,et al.  An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression. , 2005, The Journal of clinical investigation.

[30]  A. Wilkie.  Why study human limb malformations? , 2003, Journal of anatomy.

[31]  R M Winter,et al.  Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  L. Biesecker,et al.  GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome , 1997, Nature Genetics.

[33]  E. Zackai,et al.  Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. , 2005, American journal of human genetics.

[34]  Leslie G Biesecker,et al.  The Greig cephalopolysyndactyly syndrome , 2008, Orphanet journal of rare diseases.

[35]  A. Schäffer,et al.  Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. , 1997, Journal of medical genetics.

[36]  A. Joyner,et al.  A mouse model of Greig cephalapolysyndactyly syndrome: the extra-toes J mutation contains an intragenic deletion of the Gli3 gene , 1998, Nature Genetics.

[37]  L. Biesecker,et al.  What you can learn from one gene: GLI3 , 2006, Journal of Medical Genetics.

[38]  M. Kalff-Suske,et al.  Point mutations in human GLI3 cause Greig syndrome. , 1997, Human molecular genetics.

[39]  Chankyu Park,et al.  Canine Polydactyl Mutations With Heterogeneous Origin in the Conserved Intronic Sequence of LMBR1 , 2008, Genetics.

[40]  L. Biesecker,et al.  Overlap of PIV syndrome, VACTERL and Pallister–Hall syndrome: clinical and molecular analysis , 2000, Clinical genetics.

[41]  D. Ledbetter,et al.  Greig syndrome associated with an interstitial deletion of 7p: confirmation of the localization of Greig syndrome to 7p13 , 1991, Human Genetics.

[42]  Rolf Zeller,et al.  Progression of Vertebrate Limb Development Through SHH-Mediated Counteraction of GLI3 , 2002, Science.

[43]  P. Heutink,et al.  Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36 , 1999, Journal of medical genetics.