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Bone 2021 Apr 4;145:115874. Epub 2021 Feb 4.

University of South Australia, UniSA Clinical and Health Sciences, Adelaide, SA 5001, Australia; Department of Orthopedics, Tongji Hospital, Tongji University, Shanghai 200065, China; Ningbo No. 6 Hospital, Ningbo University, Ningbo 315040, China. Electronic address:

Growth plate cartilage injuries often result in bony repair at the injury site and premature mineralisation at the uninjured region causing bone growth defects, for which underlying mechanisms are unclear. With the prior microarray study showing upregulated bone morphogenetic protein (BMP) signalling during the injury site bony repair and with the known roles of BMP signalling in bone healing and growth plate endochondral ossification, this study used a rat tibial growth plate drill-hole injury model with or without systemic infusion of BMP antagonist noggin to investigate roles of BMP signalling in injury repair responses within the injury site and in the adjacent "uninjured" cartilage. At days 8, 14 and 35 post-injury, increased expression of BMP members and receptors and enhanced BMP signalling (increased levels of phosphorylated (p)-Smad1/5/8) were found during injury site bony repair. Read More

Cancer Prev Res (Phila) 2020 Oct 23. Epub 2020 Oct 23.

Hospital of the University of Pennsylvania and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Juvenile polyposis syndrome (JPS) is a clinically diagnosed hamartomatous polyposis syndrome that increases the risk of gastrointestinal cancer. Approximately 40%-50% of JPS is caused by a germline disease-causing variant (DCV) in the or genes. The aim of this study was to characterize the phenotype of DCV-negative JPS and compare it with DCV-positive JPS. Read More

Nat Commun 2019 10 4;10(1):4533. Epub 2019 Oct 4.

NIHR Oxford Biomedical Research Centre Blood Theme, University of Oxford, Oxford, UK.

Multiple myeloma is an incurable, bone marrow-dwelling malignancy that disrupts bone homeostasis causing skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, we find that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitor cells. Read More

Mol Genet Genomic Med 2019 11 7;7(11):e969. Epub 2019 Sep 7.

Division of Endocrinology, Cincinnati Children's Hospital and University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati, OH, USA.

Background: The bone morphogenetic protein (BMP) pathway is known to play an imperative role in bone, cartilage, and cardiac tissue formation. Truncating, heterozygous variants, and deletions of one of the essential receptors in this pathway, Bone Morphogenetic Protein Receptor Type1A (BMPR1A), have been associated with autosomal dominant juvenile polyposis. Heterozygous deletions have also been associated with cardiac and minor skeletal anomalies. Read More

Eur J Hum Genet 2018 11 2;26(11):1597-1602. Epub 2018 Jul 2.

Department of Genetics, F76000 and Normandie Univ, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, Rouen, France.

We have developed and validated for the diagnosis of inherited colorectal cancer (CRC) a massive parallel sequencing strategy based on: (i) fast capture of exonic and intronic sequences from ten genes involved in Mendelian forms of CRC (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, STK11, SMAD4, BMPR1A and PTEN); (ii) sequencing on MiSeq and NextSeq 500 Illumina platforms; (iii) a bioinformatic pipeline that includes BWA-Picard-GATK (Broad Institute) and CASAVA (Illumina) in parallel for mapping and variant calling, Alamut Batch (Interactive BioSoftware) for annotation, CANOES for CNV detection and finally, chimeric reads analysis for the detection of other types of structural variants (SVs). Analysis of 1644 new index cases allowed the identification of 323 patients with class 4 or 5 variants, corresponding to a 20% disease-causing variant detection rate. This rate reached 37% in patients with Lynch syndrome, suspected on the basis of tumour analyses. Read More

Fam Cancer 2017 04;16(2):195-203

Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Read More

J Mol Biol 2014 Sep 1;426(19):3221-3231. Epub 2014 Aug 1.

Berlin Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address:

Growth and differentiation factor 5 (GDF5) plays a central role in bone and cartilage development by regulating the proliferation and differentiation of chondrogenic tissue. GDF5 is synthesized as a preproprotein. The biological function of the proregion comprising 354 residues is undefined. Read More

PLoS Genet 2013 3;9(10):e1003846. Epub 2013 Oct 3.

Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany ; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p. Read More

Endocr J 2013 28;60(12):1309-19. Epub 2013 Sep 28.

Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.

Fibrodysplasia ossificans progressiva (FOP) is a skeletal disorder with progressive heterotopic ossification in skeletal muscle. A mutation causing constitutive activation in a bone morphogenetic protein (BMP) type 1 receptor [ALK2(R206H)] is found in most patients with FOP. However, the details in the heterotopic ossification of muscle in FOP and the role of matrix metalloproteinase-10 (MMP-10) in bone remain to be fully elucidated. Read More

World J Gastroenterol 2013 ;19(14):2286-92

Department of Gastroenterology and Hepatology, Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA.

Juvenile polyps are relatively common findings in children, while juvenile polyposis syndrome (JPS) is a rare hereditary syndrome entailing an increased risk of colorectal cancer. Mutations in BMPR1A or SMAD4 are found in roughly half of patients diagnosed with JPS. Mutations in PTEN gene are also found in patients with juvenile polyps and in Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome. Read More

PLoS One 2013 21;8(2):e57241. Epub 2013 Feb 21.

Pediatric Neurology Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Read More

Pediatr Surg Int 2011 Jun;27(6):617-21

National Children's Research Centre, Our Lady's Children's Hospital, Dublin 12, Ireland.

Purpose: In the chick embryo, administration of cadmium (Cd) induces omphalocele phenotype. The earliest histological changes in this model are observed commencing at 4-h post treatment (4H). The molecular mechanisms by which Cd acts during the critical period of embryogenesis remain unclear. Read More

Am J Physiol Gastrointest Liver Physiol 2010 Aug 22;299(2):G368-80. Epub 2010 Apr 22.

Dept. of Pathology and Immunology, Washington Univ. School of Medicine, St. Louis, MO 63110, USA.

The epithelium of the mammalian gastric body comprises multiple cell types replenished by a single stem cell. The adult conformation of cell lineages occurs well after birth; hence, study of genes regulating stem cell activity is facilitated by inducible systems for gene deletion. However, there is a potential pitfall involving the commonly used inducible Cre recombinase system to delete genes: we report here that induction of Cre using standard doses of tamoxifen led to marked spasmolytic polypeptide-expressing metaplasia of the stomach within days and profound atrophy of the entire epithelium with foci of hyperplasia by 2 wk even in the absence of loxP-flanked alleles. Read More

Am J Gastroenterol 2009 Dec 22;104(12):3027-33. Epub 2009 Sep 22.

Department of Colorectal Surgery, Singapore General Hospital, Singapore.

Objectives: Hereditary mixed polyposis syndrome (HMPS) is characterized by polyps of mixed adenomatous/hyperplastic/atypical juvenile histology that are autosomal dominantly inherited and that eventually lead to colorectal cancer (CRC). Although CRC with adenomatous polyps is initiated by inactivating adenomatous polyposis coli (APC), the initiating event of CRC with mixed polyps remains unclear. We aimed to identify the underlying germline defect in HMPS. Read More

Clin Genet 2009 Jan 24;75(1):79-85. Epub 2008 Sep 24.

Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Juvenile polyposis (JPS) is an autosomal dominant syndrome that predisposes individuals to develop gastrointestinal polyps and cancer. Germline point mutations in SMAD4 and BMPR1A have been identified as causing JPS in approximately 40-60% of patients, but few studies have looked at the rate of large deletions. In this study, we determined the overall prevalence of genetic changes of SMAD4 and BMPR1A by sequencing and by screening for larger deletions. Read More

Cancer Genet Cytogenet 2008 Feb;181(1):52-4

Department of Surgery, University of Iowa Carver College of Medicine, 4644 JCP, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242-1086, USA.

We describe a novel germline mutation of BMPR1A in a family with juvenile polyposis and colon cancer. This mutation consists of two consecutive substitutions (735-6 TG>AT) that cause two nonsense mutations (Y245X, G246X), inherited in an autosomal dominant fashion, on one parental chromosome. This mutation caused protein truncation, and represents a novel case of consecutive nonsense mutations in human disease. Read More

Birth Defects Res A Clin Mol Teratol 2008 Feb;82(2):63-77

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

Nonsyndromic cleft lip and palate (CLP) is among the most common human birth defects. Transmission patterns suggest that the causes are "multifactorial" combinations of genetic and nongenetic factors, mostly distinct from those causing cleft secondary palate (CP). The major etiological factors are largely unknown, and the embryological mechanisms are not well understood. Read More

Proc Natl Acad Sci U S A 2007 Jun 6;104(24):10063-8. Epub 2007 Jun 6.

Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

During the hair cycle, follicle stem cells (SCs) residing in a specialized niche called the "bulge" undergo bouts of quiescence and activation to cyclically regenerate new hairs. Developmental studies have long implicated the canonical bone morphogenetic protein (BMP) pathway in hair follicle (HF) determination and differentiation, but how BMP signaling functions in the hair follicle SC niche remains unknown. Here, we use loss and gain of function studies to manipulate BMP signaling in the SC niche. Read More

J Med Genet 2006 Mar 13;43(3):225-31. Epub 2005 Jul 13.

Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Biochemistry and Genetics, University of Copenhagen, Denmark.

Background: Brachydactyly type A2 (OMIM 112600) is characterised by hypoplasia/aplasia of the second middle phalanx of the index finger and sometimes the little finger. BDA2 was first described by Mohr and Wriedt in a large Danish/Norwegian kindred and mutations in BMPR1B were recently demonstrated in two affected families.

Methods: We found and reviewed Mohr and Wriedt's original unpublished annotations, updated the family pedigree, and examined 37 family members clinically, and radiologically by constructing the metacarpo-phalangeal profile (MCPP) pattern in nine affected subjects. Read More

J Med Genet 2004 Jul;41(7):484-91

Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242-1086, USA.

Background: Juvenile polyposis (JP) is an autosomal dominant syndrome predisposing to colorectal and gastric cancer. We have identified mutations in two genes causing JP, MADH4 and bone morphogenetic protein receptor 1A (BMPR1A): both are involved in bone morphogenetic protein (BMP) mediated signalling and are members of the TGF-beta superfamily. This study determined the prevalence of mutations in MADH4 and BMPR1A, as well as three other BMP/activin pathway candidate genes in a large number of JP patients. Read More

Genes Dev 2001 Aug;15(16):2094-110

Laboratory of Molecular Biology, NINDS, National Institutes of Health, Bethesda, Maryland 20892-4092, USA.

Bone morphogenetic proteins (BMPs) have diverse and sometimes paradoxical effects during embryonic development. To determine the mechanisms underlying BMP actions, we analyzed the expression and function of two BMP receptors, BMPR-IA and BMPR-IB, in neural precursor cells in vitro and in vivo. Neural precursor cells always express Bmpr-1a, but Bmpr-1b is not expressed until embryonic day 9 and is restricted to the dorsal neural tube surrounding the source of BMP ligands. Read More