HSCR is characterized by the congenital  absence of nerve cells in variable portions of the large intestine.  Nerve cells control bowel movement by muscle contraction.  Therefore, lack of nerve cells implies absence of peristalsis and results in accumulation of feces, dilatation of the bowel (megacolon), and obstruction.  Babies born with no nerve cells in the bowel will die unless the portion of the bowel with no nerve cells is surgically removed.  Some 1000 babies are born each year in China with HSCR and, even after surgical treatment, many patients continue to have problems such as bowel infection, blockage and soiling.  Thus, HSCR not only has tremendous psychosocial impact on the patients, but is also a heavy financial burden to the health care system.  This disease affects 1 in 5000 babies (wordwide) although is higher in Asia (1.4 in 5000)

The enteric nervous system develops before birth.  This is controlled by several genes, each with a different impact/weight on the process.  Alterations in any of these genes may result in HSCR.  Thus far, mutations have been identified in a few “main controller” genes.  However, many HSCR patients do not have mutations in these genes which implies that, in these patients, the disease may be caused by (i) severe alterations in unknown “main controlling” genes or (ii) the accumulation of less severe DNA alterations in yet unknown “minor genes”.  Possibilities (i) and (ii) can coexist and add variety to the presentation of the disease (differences in length of affected bowel, additional anomalies etc).

To uncover the genes underlying this condition we have taken two main approaches: i) candidate gene approach (investigation of a gene that may plausibly play a relevant role in the process or disease under investigation. and b) whole genome association study (examination of genetic variation across the whole genome to identify genetic associations with the disease).

Maria-Mercè GARCIA-BARCELÓ#, Clara Sze-man TANG#, Elly Sau-wai NGAN, Vincent Chi-hang LUI, Yan CHEN, Man-ting SO, Thomas Yuk-Yu LEON, Xiao-ping MIAO, Cathy Ka-yee SHUM, Feng-Qin LIU, Ming-yiu YEUNG, Zhen-wei YUAN, Wei-hong GUO, Lei LIU, Xiao-bing SUN, Liu-ming HUANG, Jin-fa TOU, You-Qiang SONG, Danny CHAN, Kenneth MC CHEUNG, Kenneth Kak-yuen WONG, Stacey S CHERNY, Pak-chung SHAM, Paul Kwong-hang TAM. Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung’s disease. PNAS 2009 (in press)

Garcia-Barceló MM, Fong PY, Tang CS, Miao XP, So MT, Yuan ZW, Li L, Guo WH, Liu L, Wang B, Sun XB, Huang LM, Tou JF, Wong KK, Ngan ES, Lui VC, Cherny SS, Sham PC, Tam PK.  Mapping of a Hirschsprung's disease locus in 3p21. Eur J Hum Genet. 2008 Jul;16(7):833-40.

Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M, Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A, Tam PK, Ceccherini I, Hofstra RM, Fernandez R; Hirschsprung Disease Consortium. Hirschsprung disease, associated syndromes and genetics: a review.  J Med Genet. 2008 Jan;45(1):1-14.

Garcia-Barceló MM, Lau DK, Ngan ES, Leon TY, Liu TT, So MT, Miao XP, Lui VC, Wong KK, Ganster RW, Cass DT, Croaker GD, Tam PK.  Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus. Ann Hum Genet. 2007 Nov;71(Pt 6):746-54.

Miao X, Garcia-Barceló MM, So MT, Leon TY, Lau DK, Liu TT, Chan EK, Lan LC, Wong KK, Lui VC, Tam PK.  Role of RET and PHOX2B gene polymorphisms in risk of Hirschsprung's disease in Chinese population. Gut. 2007 May;56(5):736.

Garcia-Barceló MM, Miao X, Lui VC, So MT, Ngan ES, Leon TY, Lau DK, Liu TT, Lao X, Guo W, Holden WT, Moore J, Tam PK. Correlation between genetic variations in Hox clusters and Hirschsprung's disease.  Ann Hum Genet. 2007 Jul;71(Pt 4):526-36.

Lui VC, Leon TY, Garcia-Barceló MM, Ganster RW, Chen BL, Hutson JM, Tam PK. Novel RET mutation produces a truncated RET receptor lacking the intracellular signaling domain in a 3-generation family with Hirschsprung disease.  Clin Chem. 2005 Aug;51(8):1552-4.

Tam PK, Garcia-Barcelo M. Molecular genetics of Hirschsprung's disease. Semin Pediatr Surg. 2004 Nov;13(4):236-48. Review.

Garcia-Barcelo M, Ganster RW, Lui VC, Leon TY, So MT, Lau AM, Fu M, Sham MH,  Knight J, Zannini MS, Sham PC, Tam PK.  TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease.  Hum Mol Genet. 2005 Jan 15;14(2):191-204.

Garcia-Barceló MM, Lee WS, Sham MH, Lui VC, Tam PK. Is there a role for the IHH gene in Hirschsprung's disease?  Neurogastroenterol Motil. 2003 Dec;15(6):663-8.

Garcia-Barceló M, Sham MH, Lee WS, Lui VC, Chen BL, Wong KK, Wong JS, Tam PK.  Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease.  Clin Chem. 2004 Jan;50(1):93-100.

Garcia-Barceló MM, Sham MH, Lui VC, Chen BL, Song YQ, Lee WS, Yung SK, Romeo G, Tam PK. Chinese patients with sporadic Hirschsprung's disease are predominantly represented by a single RET haplotype. J Med Genet. 2003 Nov;40(11):e122.

Garcia-Barceló M, Sham MH, Lui VC, Chen BL, Ott J, Tam PK. Association study of PHOX2B as a candidate gene for Hirschsprung's disease. Gut. 2003 Apr;52(4):563-7.

Aging is the age-related deterioration of physiological functions necessary for survival and fertility. As normal aging progresses over a long period of time, making it difficult to study, premature/precocious aging becomes ideal models for aging research. HGPS and a related mouse model, Zmpste24 deficiency, share many aging features with the natural aging process. Our previous studies showed that accumulation of DNA damage and cellular senescence is attributable to defective recruitment of checkpoint response/repair proteins that leads to chromosomal instability. To gain more insight into the molecular mechanisms underlying aging process, we will utilize laminopathy-based premature aging mice and C. elegans to identify and to test some of the molecular signature and changes contributing to natural aging.

We propose to form a multidisciplinary team to utilize our expertise in different model systems, gene inactivation/transgenesis, bioinformatics, imaging analysis, cell biology, protein biochemistry, stem cells biology to tackle important issues on aging. The scope and the complexity of the proposed project require multidisciplinary expertise that can only be achieved by a well coordinated close collaboration of several research teams. The rationale for a group research in the proposed project is as following: Groups involved in this project already have a track record of collaboration or have already initiated collaboration on aging and stem cell research. Exciting data have already been generated through the initial collaboration and further close collaboration will facilitate the existing coordinated efforts in understanding several key issues in aging, particularly the common molecular mechanisms that contribute to premature aging and natural aging processes. We have an animal model for human premature aging (HGPS) research and a strong track record in mouse genetics and in aging-related research. We expect international recognition in aging research for our contribution to the knowledge of molecular control of aging.

Kandert S, Lüke Y, Kleinhenz T, Neumann S, Lu W, Jaeger VM, Munck M, Wehnert M, Müller CR, Zhou Z, Noegel AA, Dabauvalle MC and Karakesisoglou I Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells.
Human Molecular Genetics 2007 16(23):2944-2959

Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadinanos J, Lopez-Otin C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z.* Genomic instability in laminopathy-based premature aging. Nature Medicine 2005, 11 (7), 780-785 * correspondence
Comment by Misteli T, Scaffidi P. In Nat Med 2005 11(7):718-9
Genome instability in progeria: when repair gets old.
Recommended by Faculty 1000 by two members, F1000 Factor 6.4
Tom Misteli: This study points to a potential molecular mechanism for the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS).
Yosef Gruenbaum: This exciting paper provides evidence that unprocessed lamin A and truncated lamin A cause aberrant DNA damage response and repair, resulting in genomic instability.

Varela I, Cadinanos J, Pendas AM, Gutierrez-Fernandez A, Folgueras AR, Sanchez LM, Zhou Z, Rodriguez FJ, Stewart CL, Vega JA, Tryggvason K, Freije JM, Lopez-Otin C. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 2005 437(7058):564-8 (14 citations)
Recommended by Faculty 1000 by M. Sharon Stack, F1000 Factor 6.0
This study provides an intriguing link between ageing and tumor suppression.

Pendás A, Zhou Z *, Cadinanos J, Freije JM, Wang J, Hultenby K, Astudillo A, Wernerson A, Rodriguez F, Tryggvason K, Lopez-Otin C. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase–deficient mice. Nature Genetics 2002; 31(1): 94-99 *Equal contribution