A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family

Liu, Mugen; Wang, Xu; Cai, Zhou; Tang, Zhaohui; Cao, Kangsheng; Liang, Bo; Ren, Xiang; Liu, Jingyu; Wang, Qing Kenneth

doi:10.1007/s10038-006-0012-6

Cited by 32 publications

(29 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The absence of an intact zinc site in dHhN remains curious, but perhaps suggests that it is the large substrate-binding cleft rather than the zinc ion itself that is most essential for mediating HhN-Ptc interactions. Indeed, mutation of Hhip D383 to alanine does not completely abolish binding between Hhip and ShhN (Bishop et al 2009;Bosanac et al 2009), and several mutations in the IhhN zinc cleft have been identified recently in BDA1 patients (Liu et al 2006;Byrnes et al 2009). …”

Section: Resultsmentioning

confidence: 99%

Interactions between Hedgehog proteins and their binding partners come into view

Beachy¹,

Hymowitz²,

Lazarus³

et al. 2010

Genes Dev.

190

158

View full text Add to dashboard Cite

Hedgehog (Hh) proteins are secreted signaling molecules that mediate essential tissue-patterning events during embryonic development and function in tissue homeostasis and regeneration throughout life. Hh signaling is regulated by multiple mechanisms, including covalent lipid modification of the Hh protein and interactions with multiple protein and glycan partners. Unraveling the nature and effects of these interactions has proven challenging, but recent structural and biophysical studies of Hh proteins and active fragments of heparin, Ihog, Cdo, Boc, Hedgehog-interacting protein (Hhip), Patched (Ptc), and the monoclonal antibody 5E1 have added a new level of molecular detail to our understanding of how Hh signal response and distribution are regulated within tissues. We review these results and discuss their implications for understanding Hh signaling in normal and disease states.

show abstract

Section: Resultsmentioning

confidence: 99%

Interactions between Hedgehog proteins and their binding partners come into view

Beachy¹,

Hymowitz²,

Lazarus³

et al. 2010

Genes Dev.

190

158

View full text Add to dashboard Cite

show abstract

“…The first group affects the calcium-binding region of Ihh and include E95K, E95G, D100N, D100E, and E131K (22,33). A second category, R128N, T154I, and T130N, interrupts hydrogen-bonding networks formed between IhhN and Asp 872 of CDO or the equivalent residue, Asp 758 , of BOC (34,35). Superposition of IhhN on DhhN in the DhhN⅐Hip structure suggests that these mutations would also disrupt a similar hydrogen-bonding network involving Glu 380 of Hip (32,36) and thus be likely to disrupt interactions between HhN proteins and multiple binding partners.…”

Section: Resultsmentioning

confidence: 99%

All Mammalian Hedgehog Proteins Interact with Cell Adhesion Molecule, Down-regulated by Oncogenes (CDO) and Brother of CDO (BOC) in a Conserved Manner

Kavran

Ward

Oladosu

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

These results show that all mammalian Hh proteins bind CDO and BOC in the same manner. We also show that interactions between Hh proteins and CDO are weakened at low pH. Formation of Hh-mediated Hh oligomers is thought to be an important feature of normal Hh signaling, but no conserved self-interaction between Hh proteins is apparent from inspection of 14 independent Hh-containing crystal lattices.Hedgehog (Hh) 2 signaling proteins mediate key cell differentiation and tissue patterning events during animal development (1-3). Hh proteins generate tissue pattern, and fit the classical definition of a morphogen, by forming concentration gradients emanating from sites of secretion and eliciting different cell fate responses at different concentrations (3, 4). Three Hh homologs are present in mammals: Sonic Hh (Shh), Indian Hh (Ihh), and Desert Hh (Dhh), but only a single Hh protein is present in Drosophila. Shh is essential for normal development of the nervous system, skeleton, and limbs (3). Ihh and Dhh are required for normal skeletal and testis development, respectively (5, 6). Hh proteins also play a role in maintenance and regeneration of adult tissues and stem cells (7,8), and abnormal Hh signaling has been implicated in several cancers (9). Drugs targeting the Hh pathway are currently in late stage clinical trials for the treatment of basal cell carcinoma (10) and early stage trials for treatment of breast, pancreatic, ovarian, brain, and gastric cancers (10, 11).Hh distribution and responsiveness are tightly regulated, and many factors influence the secretion, movement, and reception of Hh signals (12, 13). Hh proteins are synthesized as 45-kDa precursors that cleave themselves to generate an N-terminal 19-kDa fragment (HhN) and a C-terminal 25-kDa fragment (HhC). HhC mediates this reaction, which also results in the covalent attachment of cholesterol to the C terminus of HhN (14). HhN is palmitoylated at its N terminus in a separate reaction, and dually lipidated HhN is secreted as part of a multivalent lipoprotein particle (13,15). HhN mediates all known Hh signaling activities, and HhN lipidation and multivalency are required both for full potency and to regulate the distribution of HhN (12). Reception of the Hh signal involves Patched (Ptc) (16), a 12-pass integral membrane protein with homology to proton-driven bacterial transporters, and Smoothened (17), a 7-pass integral membrane protein with homology to G-protein coupled receptors. In the absence of Hh, Ptc inhibits the activity of Smoothened (17). Hh relieves this inhibition, resulting in the activation of Smoothened and downstream effectors that converge on Gli family transcription factors to alter expression levels of target genes (17).Despite high sequence similarity between Hh proteins, not all interactions between Hh proteins and cell-surface receptors are conserved between vertebrates and invertebrates. Vertebrate Hh proteins appear to interact directly with cognate Ptc proteins, but a direct interaction between the N-terminal signaling domai...

show abstract

“…In one family, the feet were reported to be normal; however, lower limb X-rays were not provided in the paper. 22 The involvement of the phalanges and metacarpals (metatarsals) is quite variable even within the same family. Shortening of the first metacarpal, which is typically a distinguishing feature of Brachydactyly type C is a rare but reported finding.…”

Section: Mutations In Indian Hedgehog That Causes Brachydactyle A-1mentioning

confidence: 99%

“…20,21 The only reported BDA1-causing mutation that was not restricted to codons 95, 100, and 131 of IHH is p.Thr154Ile. 22 All four of these codons are highly conserved ( Figure 1 suggests that they may reside in a region of IHH that is of particular importance and is responsible for the normal functioning of the growth plate during bone development.…”

Section: Introductionmentioning

confidence: 99%

Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog

et al. 2009

View full text Add to dashboard Cite

Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we also describe a New Zealand family, which carries the 'Farabee' founder mutation and haplotype. All of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH and are in contrast to those mutations causing an autosomal recessive acrocapitofemoral dysplasia, whose mutations are located at the distal N-and C-terminal regions of IHH-N and are physically separated from the BDA1-causing mutations. The identification of multiple independent mutations in codons 95, 100, and now in 131, implicate a discrete function for this region of the protein. Finally, we present a clinical review of all reported and confirmed cases of BDA1, highlighting features of the disorder, which add to the spectrum of the IHH mutations.

show abstract

A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family

Cited by 32 publications

References 11 publications

Interactions between Hedgehog proteins and their binding partners come into view

Interactions between Hedgehog proteins and their binding partners come into view

All Mammalian Hedgehog Proteins Interact with Cell Adhesion Molecule, Down-regulated by Oncogenes (CDO) and Brother of CDO (BOC) in a Conserved Manner

Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog

Contact Info

Product

Resources

About