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1.  The use of lectins as markers for differentiated secretory cells in planarians 
Freshwater planarians have reemerged as excellent models to investigate mechanisms underlying regeneration. The introduction of molecular tools has facilitated the study of planarians, but cell- and tissue-specific markers are still needed to examine differentiation of most cell types. Here we report the utility of fluorescent lectin-conjugates to label tissues in the planarian Schmidtea mediterranea. We show that 16 lectin-conjugates stain planarian cells or tissues; 13 primarily label the secretory cells, their cytoplasmic projections, and terminal pores. Thus, we examined regeneration of the secretory system using lectin markers and functionally characterized two genes expressed in the secretory cells: marginal adhesive gland-1 (mag-1) and Smed-reticulocalbin1 (Smed-rcn1). RNAi knockdown of these genes caused a dramatic reduction of secretory cell lectin staining, suggesting a role for mag-1 and Smed-rcn1 in secretory cell differentiation. Our results provide new insights into planarian secretory system regeneration and add new markers for labeling several planarian tissues.
PMCID: PMC3004010  PMID: 20865784
Planarian; Schmidtea mediterranea; lectin; regeneration; Platyhelminthes; flatworms
2.  Tissue absence initiates regeneration through Follistatin-mediated inhibition of Activin signaling 
eLife  2013;2:e00247.
Regeneration is widespread, but mechanisms that activate regeneration remain mysterious. Planarians are capable of whole-body regeneration and mount distinct molecular responses to wounds that result in tissue absence and those that do not. A major question is how these distinct responses are activated. We describe a follistatin homolog (Smed-follistatin) required for planarian regeneration. Smed-follistatin inhibition blocks responses to tissue absence but does not prevent normal tissue turnover. Two activin homologs (Smed-activin-1 and Smed-activin-2) are required for the Smed-follistatin phenotype. Finally, Smed-follistatin is wound-induced and expressed at higher levels following injuries that cause tissue absence. These data suggest that Smed-follistatin inhibits Smed-Activin proteins to trigger regeneration specifically following injuries involving tissue absence and identify a mechanism critical for regeneration initiation, a process important across the animal kingdom.
eLife digest
Most animals can respond to injury with some form of tissue regeneration. In mammals, this is limited to wound healing, whereas other vertebrates—such as salamanders and zebrafish—can regenerate parts of internal organs and even entire appendages. The planarian, a flatworm, is even more remarkable, being able to regenerate its head or tail following amputation, and even a whole animal from just a small body fragment. This is particularly impressive given that planarians have a complex internal anatomy, which includes muscles, intestines, a system similar to kidneys, and a central nervous system with a brain.
How is such regeneration accomplished? Why are planarians able to regenerate their bodies so extensively, whereas humans cannot? To what extent are the mechanisms of planarian regeneration common to other animals? These questions have driven the study of planarian regeneration for more than a century, but it is only in recent years that the tools needed to address these questions at the molecular level have become available.
Planarian regeneration proceeds over several days and involves multiple processes, including gene expression, cell division and cell death. Importantly, it has recently been shown that planarians activate different responses depending on whether an injury results in significant tissue loss—and therefore requires regeneration for repair—or if simple wound healing will be sufficient. The mechanisms behind these different responses to injury have, however, remained a mystery.
Now, Gaviño et al. have identified a key mechanism in the initiation of regeneration following tissue loss. This is centered on the gene follistatin, which is expressed following wounding. When genetic techniques are used to disrupt the expression of follistatin, regeneration is completely blocked. However, the animal’s ability to routinely replace old cells via a stem-cell mediated mechanism is unaffected. This indicates that follistatin is specifically required for the replacement of cells lost through injury. Gaviño et al. further demonstrate that the protein encoded by follistatin likely initiates tissue regeneration upon substantial tissue loss through inhibition of proteins called Activins.
Activin and Follistatin proteins are broadly conserved in evolution, and are also expressed in mammals, raising the possibility that similar molecular circuits may govern regenerative responses in many species.
PMCID: PMC3771573  PMID: 24040508
planarian regeneration; wound signaling; Follistatin; Activin; Other
3.  Loss of DNA Mismatch Repair Imparts a Selective Advantage in Planarian Adult Stem Cells 
PLoS ONE  2011;6(7):e21808.
Lynch syndrome (LS) leads to an increased risk of early-onset colorectal and other types of cancer and is caused by germline mutations in DNA mismatch repair (MMR) genes. Loss of MMR function results in a mutator phenotype that likely underlies its role in tumorigenesis. However, loss of MMR also results in the elimination of a DNA damage-induced checkpoint/apoptosis activation barrier that may allow damaged cells to grow unchecked. A fundamental question is whether loss of MMR provides pre-cancerous stem cells an immediate selective advantage in addition to establishing a mutator phenotype. To test this hypothesis in an in vivo system, we utilized the planarian Schmidtea mediterranea which contains a significant population of identifiable adult stem cells. We identified a planarian homolog of human MSH2, a MMR gene which is mutated in 38% of LS cases. The planarian Smed-msh2 is expressed in stem cells and some progeny. We depleted Smed-msh2 mRNA levels by RNA-interference and found a striking survival advantage in these animals treated with a cytotoxic DNA alkylating agent compared to control animals. We demonstrated that this tolerance to DNA damage is due to the survival of mitotically active, MMR-deficient stem cells. Our results suggest that loss of MMR provides an in vivo survival advantage to the stem cell population in the presence of DNA damage that may have implications for tumorigenesis.
PMCID: PMC3128615  PMID: 21747960
4.  The Zn Finger protein Iguana impacts Hedgehog signaling by promoting ciliogenesis 
Developmental biology  2009;337(1):148-156.
Hedgehog signaling is critical for metazoan development and requires cilia for pathway activity. The gene iguana was discovered in zebrafish as required for Hedgehog signaling, and encodes a novel Zn finger protein. Planarians are flatworms with robust regenerative capacities and that utilize epidermal cilia for locomotion. RNA interference of Smed-iguana in the planarian S. mediterranea caused cilia loss and failure to regenerate new cilia, but did not cause defects similar to those observed in hedgehog(RNAi) animals. Smed-iguana gene expression was also similar in pattern to the expression of multiple other ciliogenesis genes, but was not required for expression of these ciliogenesis genes. iguana-defective zebrafish had too few motile cilia in pronephric ducts and in Kupffer's vesicle. Kupffer's vesicle promotes left-right asymmetry and iguana mutant embryos had left-right asymmetry defects. Finally, human Iguana proteins (dZIP1 and dZIP1L) localize to the basal bodies of primary cilia and, together, are required for primary cilia formation. Our results indicate that a critical and broadly conserved function for Iguana is in ciliogenesis and that this function has come to be required for Hedgehog signaling in vertebrates.
PMCID: PMC2799895  PMID: 19852954
5.  Mild Campomelic Dysplasia: Report on a Case and Review 
Molecular Syndromology  2011;1(4):163-168.
We report on a 10.5-year-old girl with a mild form of campomelic dysplasia. She presented with short stature of prenatal onset, dysmorphic facial features, limitation of supination and pronation of the forearms, dysplastic nails, and bone abnormalities consisting especially of cone-shaped epiphyses of the middle phalanx of the 2nd fingers, brachydactyly and clinodactyly of the middle phalanx of both 5th fingers, short 4th metacarpals, radial and femoral head subluxation, hypoplastic scapulae, humeral and ulnar epiphyseal abnormalities, unossified symphysis pubis, and a significant delay in bone age. Molecular analysis of the SOX9 gene revealed the presence of a de novo missense mutation: p.P170L (c.509C>T). Mild and surviving cases of campomelic dysplasia are reviewed.
PMCID: PMC3042119  PMID: 21373255
Bone dysplasia; Dysmorphology; Malformations; Mental retardation; SOX9
6.  Novel Compound Heterozygous Mutations in the Cathepsin K Gene in Japanese Female Siblings with Pyknodysostosis 
Molecular Syndromology  2012;2(6):254-258.
We report on female siblings with pyknodysostosis who showed common clinical and radiographic features including disproportionate short stature, dental abnormalities, increased bone density, open fontanelle, and acroosteolysis. Sequence analysis of the cathepsin K (CTSK) gene demonstrated compound heterozygous mutations (935 C>T, A277V and 489 G>C, R122P) in the affected siblings and a heterozygous mutation in their parents. The former missense mutation has previously been reported in 6 unrelated patients, and the latter seemed to be a novel mutation. Atomic model assessment of the CTSK gene revealed that the R122P mutant could disrupt hydrogen bonds binding with chondroitin 4-sulfate leading to a decrease in the collagen-degrading activity of cathepsin K.
PMCID: PMC3362291  PMID: 22822386
Cathepsin K; Chondroitin 4-sulfate; Compound heterozygous mutations; Pyknodysostosis
Human molecular genetics  2008;17(14):2244-2254.
Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant craniofacial and skeletal dysplasia that is caused by mutations involving the TRPS1 gene. Patients with TRPS have short stature, hip abnormalities, cone-shaped epiphyses, and premature closure of growth plates reflecting defects in endochondral ossification. The TRPS1 gene encodes for the transcription factor TRPS1 that has been demonstrated to repress transcription in vitro. To elucidate molecular mechanisms underlying skeletal abnormalities in TRPS, we analyzed Trps1 mutant mice (Trps1ΔGT mice). Analyses of growth plates demonstrated delayed chondrocyte differentiation and accelerated mineralization of perichondrium in Trps1 mutant mice. These abnormalities were accompanied by increased Runx2 and Ihh expression and increased Ihh signaling. We demonstrated that Trps1 physically interacts with Runx2 and represses Runx2-mediated transactivation. Importantly, generation of Trps1ΔGT/+; Runx2+/− double heterozygous mice rescued the opposite growth plate phenotypes of single mutants demonstrating the genetic interaction between Trps1 and Runx2 transcription factors. Collectively, these data suggest that skeletal dysplasia in TRPS is caused by dysregulation of chondrocyte and perichondrium development partially due to loss of Trps1 repression of Runx2.
PMCID: PMC2710999  PMID: 18424451
8.  Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome 
Human Molecular Genetics  2008;17(14):2244-2254.
Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant craniofacial and skeletal dysplasia that is caused by mutations involving the TRPS1 gene. Patients with TRPS have short stature, hip abnormalities, cone-shaped epiphyses and premature closure of growth plates reflecting defects in endochondral ossification. The TRPS1 gene encodes for the transcription factor TRPS1 that has been demonstrated to repress transcription in vitro. To elucidate the molecular mechanisms underlying skeletal abnormalities in TRPS, we analyzed Trps1 mutant mice (Trps1ΔGT mice). Analyses of growth plates demonstrated delayed chondrocyte differentiation and accelerated mineralization of perichondrium in Trps1 mutant mice. These abnormalities were accompanied by increased Runx2 and Ihh expression and increased Indian hedgehog signaling. We demonstrated that Trps1 physically interacts with Runx2 and represses Runx2-mediated trans-activation. Importantly, generation of Trps1ΔGT/+;Runx2+/− double heterozygous mice rescued the opposite growth plate phenotypes of single mutants, demonstrating the genetic interaction between Trps1 and Runx2 transcription factors. Collectively, these data suggest that skeletal dysplasia in TRPS is caused by dysregulation of chondrocyte and perichondrium development partially due to loss of Trps1 repression of Runx2.
PMCID: PMC2710999  PMID: 18424451
9.  Spondyloepiphyseal dysplasia. 
Journal of Medical Genetics  1983;20(2):117-121.
Skeletal dysplasia with autosomal dominant inheritance was found in four members of one family and in one sporadic case. The syndrome comprises brachydactyly E, platyspondyly, abnormality of the sacroiliac joint, disturbance of metaphyseal modelling, epiphyseal dysplasia, and short stature. This study deals with a particular type of spondyloepiphyseal dysplasia and compares it with similar cases in two previously published papers.
PMCID: PMC1049012  PMID: 6405037
10.  TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype 
Holt–Oram syndrome (HOS) is a rare autosomal dominant heart–hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3–10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2–9 of the TBX5 gene, with breakpoints within introns 1–2 and 9–10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.
PMCID: PMC3400730  PMID: 22333898
Holt–Oram syndrome; TBX5; duplication; array-CGH; congenital heart disease; limb anomalies
11.  Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor 
ACS Chemical Biology  2013;8(10):2145-2150.
The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 Å DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the ‘DFG-out’ conformation and inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with good selectivity as assessed against a panel of 451 kinases measured using the KinomeScan technology. We identified a mutation in the hinge region of DDR1, G707A, that confers >20-fold resistance to the ability of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to establish what pharmacology is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction.
PMCID: PMC3800496  PMID: 23899692
12.  Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis 
Human Molecular Genetics  2012;21(22):4904-4909.
Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. At the histopathological level, there is a paucity of osteoclasts when the disease presents. In two patients with DSS, we identified homozygous or compound heterozygous missense mutations in SLC29A3 by whole-exome sequencing. This gene encodes a nucleoside transporter, mutations in which cause histiocytosis–lymphadenopathy plus syndrome, a group of conditions with little or no skeletal involvement. This transporter is essential for lysosomal function in mice. We demonstrate the expression of Slc29a3 in mouse osteoclasts in vivo. In monocytes from patients with DSS, we observed reduced osteoclast differentiation and function (demineralization of calcium surface). Our report highlights the pleomorphic consequences of dysfunction of this nucleoside transporter, and importantly suggests a new mechanism for the control of osteoclast differentiation and function.
PMCID: PMC3607481  PMID: 22875837
13.  Identification of Mutations Underlying 20 Inborn Errors of Metabolism in the United Arab Emirates Population 
Inborn errors of metabolism (IEM) are frequently encountered by physicians in the United Arab Emirates (UAE). However, the mutations underlying a large number of these disorders have not yet been determined. Therefore, the objective of this study was to identify the mutations underlying a number of IEM disorders among UAE residents from both national and expatriate families. A case series of patients from 34 families attending the metabolic clinic at Tawam Hospital were clinically evaluated, and molecular testing was carried out to determine their causative mutations. The mutation analysis was carried out at molecular genetics diagnostic laboratories. Thirty-eight mutations have been identified as responsible for twenty IEM disorders, including in the metabolism of amino acids, lipids, steroids, metal transport and mitochondrial energy metabolism, and lysosomal storage disorders. Nine of the identified mutations are novel, including two missense mutations, three premature stop codons and four splice site mutations. Mutation analysis of IEM disorders in the UAE population has an important impact on molecular diagnosis and genetic counseling for families affected by these disorders.
PMCID: PMC3354585  PMID: 22106832
14.  A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia 
Human Molecular Genetics  2009;19(1):52-64.
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias belonging to the same bone dysplasia family. PSACH is characterized by generalized epi-metaphyseal dysplasia, short-limbed dwarfism, joint laxity and early onset osteoarthritis. MED is a milder disease with radiographic features often restricted to the epiphyses of the long bones. PSACH and some forms of MED result from mutations in cartilage oligomeric matrix protein (COMP), a pentameric glycoprotein found in cartilage, tendon, ligament and muscle. PSACH-MED patients often have a mild myopathy characterized by mildly increased plasma creatine kinase levels, a variation in myofibre size and/or small atrophic fibres. In some instances, patients are referred to neuromuscular clinics prior to the diagnosis of an underlying skeletal dysplasia; however, the myopathy associated with PSACH-MED has not previously been studied. In this study, we present a detailed study of skeletal muscle, tendon and ligament from a mouse model of mild PSACH harbouring a COMP mutation. Mutant mice exhibited a progressive muscle weakness associated with an increased number of muscle fibres with central nuclei at the perimysium and at the myotendinous junction. Furthermore, the distribution of collagen fibril diameters in the mutant tendons and ligaments was altered towards thicker collagen fibrils, and the tendons became more lax in cyclic strain tests. We hypothesize that the myopathy in PSACH-MED originates from an underlying tendon and ligament pathology that is a direct result of structural abnormalities to the collagen fibril architecture. This is the first comprehensive characterization of the musculoskeletal phenotype of PSACH-MED and is directly relevant to the clinical management of these patients.
PMCID: PMC2792148  PMID: 19808781
15.  Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development 
Human Molecular Genetics  2008;18(1):193-201.
Missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, cause clinically similar but distinctive disorders, LEOPARD (LS) and Noonan (NS) syndromes. The LS is an autosomal dominant disorder with pleomorphic developmental abnormalities including lentigines, cardiac defects, short stature and deafness. Biochemical analyses indicated that LS alleles engender loss-of-function (LOF) effects, while NS mutations result in gain-of-function (GOF). These biochemical findings lead to an enigma that how PTPN11 mutations with opposite effects on function result in disorders that are so similar. To study the developmental effects of the commonest LS PTPN11 alleles (Y279C and T468M), we generated LS transgenic fruitflies using corkscrew (csw), the Drosophila orthologue of PTPN11. Ubiquitous expression of the LS csw mutant alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were GOF phenotypes mediated by increased RAS/MAPK signaling and requiring the LS mutant’s residual phosphatase activity. Our findings provide the first evidence that LS mutant alleles have GOF developmental effects despite reduced phosphatase activity, providing a rationale for how PTPN11 mutations with GOF and LOF produce similar but distinctive syndromes.
PMCID: PMC2644650  PMID: 18849586
16.  A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance 
We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26.
In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation.
Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia.
We report the first missense homozygous disease-causing mutation in KIF7 and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients.
PMCID: PMC3492204  PMID: 22587682
KIF7; Acrocallosal; Joubert; Sonic hedgehog; Dysmorphism; Multiple epiphyseal dysplasia; Fetal hydrolethalus
17.  Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma 
British Journal of Cancer  2007;96(5):808-814.
The discoidin domain receptors, (DDR)1 and DDR2, have been linked to numerous human cancers. We sought to determine expression levels of DDRs in human lung cancer, investigate prognostic determinates, and determine the prevalence of recently reported mutations in these receptor tyrosine kinases. Tumour samples from 146 non-small cell lung carcinoma (NSCLC) patients were analysed for relative expression of DDR1 and DDR2 using quantitative real-time PCR (qRT-PCR). An additional 23 matched tumour and normal tissues were tested for differential expression of DDR1 and DDR2, and previously reported somatic mutations. Discoidin domain receptor 1 was found to be significantly upregulated by 2.15-fold (P=0.0005) and DDR2 significantly downregulated to an equivalent extent (P=0.0001) in tumour vs normal lung tissue. Discoidin domain receptor 2 expression was not predictive for patient survival; however, DDR1 expression was significantly associated with overall (hazard ratio (HR) 0.43, 95% CI=0.22–0.83, P=0.014) and disease-free survival (HR=0.56, 95% CI=0.33–0.94, P=0.029). Multivariate analysis revealed DDR1 is an independent favourable predictor for prognosis independent of tumour differentiation, stage, histology, and patient age. However, contrary to previous work, we did not observe DDR mutations. We conclude that whereas altered expression of DDRs may contribute to malignant progression of NSCLC, it is unlikely that this results from mutations in the DDR1 and DDR2 genes that we investigated.
PMCID: PMC2360060  PMID: 17299390
lung cancer; DDR1; DDR2; mutation
18.  Analysis of sequence variations in low-density lipoprotein receptor gene among Malaysian patients with familial hypercholesterolemia 
BMC Medical Genetics  2011;12:40.
Familial hypercholesterolemia is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor gene. Few and limited analyses of familial hypercholesterolemia have been performed in Malaysia, and the underlying mutations therefore remain largely unknown.
We studied a group of 154 unrelated FH patients from a northern area of Malaysia (Kelantan). The promoter region and exons 2-15 of the LDLR gene were screened by denaturing high-performance liquid chromatography to detect short deletions and nucleotide substitutions, and by multiplex ligation-dependent probe amplification to detect large rearrangements.
A total of 29 gene sequence variants were reported in 117(76.0%) of the studied subjects. Eight different mutations (1 large rearrangement, 1 short deletion, 5 missense mutations, and 1 splice site mutation), and 21 variants. Eight gene sequence variants were reported for the first time and they were noticed in familial hypercholesterolemic patients, but not in controls (p.Asp100Asp, p.Asp139His, p.Arg471Gly, c.1705+117 T>G, c.1186+41T>A, 1705+112C>G, Dup exon 12 and p.Trp666ProfsX45). The incidence of the p.Arg471Gly variant was 11%. Patients with pathogenic mutations were younger, had significantly higher incidences of cardiovascular disease, xanthomas, and family history of hyperlipidemia, together with significantly higher total cholesterol and low density lipoprotein levels than patients with non-pathogenic variants.
Twenty-nine gene sequence variants occurred among FH patients; those with predicted pathogenicity were associated with higher incidences of cardiovascular diseases, tendon xanthomas, and higher total and low density lipoprotein levels compared to the rest. These results provide preliminary information on the mutation spectrum of this gene among patients with FH in Malaysia.
PMCID: PMC3071311  PMID: 21418584
19.  Novel Mutations in GJA1 Cause Oculodentodigital Syndrome 
Journal of dental research  2008;87(11):1021-1026.
Oculodentodigital syndrome (ODD) is a rare, usually autosomal-dominant disorder that is characterized by developmental abnormalities of the face, eyes, teeth, and limbs. The most common clinical findings include a long, narrow nose, short palpebral fissures, type III syndactyly, and dental abnormalities including generalized microdontia and enamel hypoplasia. Recently, it has been shown that mutations in the gene GJA1, which encodes the gap junction protein connexin 43, underlie oculodentodigital syndrome. Gap junction communication between adjacent cells is known to be vital during embryogenesis and subsequently for normal tissue homeostasis. Here, we report 8 missense mutations in the coding region of GJA1, 6 of which have not been described previously, in ten unrelated families diagnosed with ODD. In addition, immunofluorescence analyses of a developmental series of mouse embryos and adult tissue demonstrates a strong correlation between the sites of connexin 43 expression and the clinical phenotype displayed by individuals affected by ODD.
PMCID: PMC2588666  PMID: 18946008
Oculodentodigital syndrome; ODD; GJA1; Connexin 43
20.  HP1 promotes tumor suppressor BRCA1 functions during the DNA damage response 
Nucleic Acids Research  2013;41(11):5784-5798.
The DNA damage response (DDR) involves both the control of DNA damage repair and signaling to cell cycle checkpoints. Therefore, unraveling the underlying mechanisms of the DDR is important for understanding tumor suppression and cellular resistance to clastogenic cancer therapeutics. Because the DDR is likely to be influenced by chromatin regulation at the sites of DNA damage, we investigated the role of heterochromatin protein 1 (HP1) during the DDR process. We monitored double-strand breaks (DSBs) using the γH2AX foci marker and found that depleting cells of HP1 caused genotoxic stress, a delay in the repair of DSBs and elevated levels of apoptosis after irradiation. Furthermore, we found that these defects in repair were associated with impaired BRCA1 function. Depleting HP1 reduced recruitment of BRCA1 to DSBs and caused defects in two BRCA1-mediated DDR events: (i) the homologous recombination repair pathway and (ii) the arrest of cell cycle at the G2/M checkpoint. In contrast, depleting HP1 from cells did not affect the non-homologous end-joining (NHEJ) pathway: instead it elevated the recruitment of the 53BP1 NHEJ factor to DSBs. Notably, all three subtypes of HP1 seemed to be almost equally important for these DDR functions. We suggest that the dynamic interaction of HP1 with chromatin and other DDR factors could determine DNA repair choice and cell fate after DNA damage. We also suggest that compromising HP1 expression could promote tumorigenesis by impairing the function of the BRCA1 tumor suppressor.
PMCID: PMC3675466  PMID: 23589625
21.  X-Linked Spondyloepiphyseal Dysplasia Tarda: Identification of a TRAPPC2 Mutation in a Korean Pedigree 
Annals of Laboratory Medicine  2012;32(3):234-237.
Spondyloepiphyseal dysplasia (SED) comprises a heterogeneous group of skeletal dysplasias that primarily affect the epiphyses and vertebral bodies. Patients affected by SED usually exhibit short stature and experience early development of degenerative osteoarthritis. SED is subdivided into congenita and tarda forms according to the age at onset and clinical severity, and further subdivided into genetically different forms according to the mode of inheritance and the gene involved. We report a 14-yr-old Korean male who presented with a disproportionately short stature and a short trunk. A pedigree analysis of 3 generations with 6 affected persons revealed an X-linked recessive mode of inheritance. Mutation analysis of the TRAPPC2 (previously called SEDL) gene, the only gene associated with X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT; MIM 313400), was performed, and a splice-donor site mutation in intron 3 of the TRAPPC2 gene (c.93+5G>A) was identified in the proband and in his unaffected mother (a heterozygote). This mutation is one of the 2 most frequent mutations reported in the medical literature, and is known to result in exon 3 skipping. This is the first report of a genetically confirmed X-linked SEDT case in Korea and highlights the importance of recognizing the mode of inheritance in the diagnosis of X-linked SEDT.
PMCID: PMC3339307  PMID: 22563562
Spondyloepiphyseal dysplasia; X-linked spondyloepiphyseal dysplasia tarda; TRAPPC2; SEDL
22.  Acroform type of enchondromatosis associated with severe vertebral involvement and facial dysmorphism in a boy with a new variant of enchondromatosis type I1 of Spranger: case report and a review of the literature 
Cases Journal  2008;1:324.
Enchondromatosis represent a heterogenous group of disorders. Spranger et al attempted a classification into 6 types: Ollier disease, Maffuci syndrome, metachondromatosis, spondyloenchondrodysplasia, enchondromatosis with irregular vertebral lesions, and generalized enchondromatosis. Halal and Azouz added 3 tentative categories to the 6 in the classification of Spranger et al.
Case presentation
We report on a 15-year-old boy with acrofrom upper limbs and mixed appearance of radiolucency, cysts and striae of fibro-chondromatosis. Lower limbs (femoral, tibial and fibular dysplasia showed enlarged metaphyses near the knees bilaterally) were present. Additional features of short stature, macrocephaly, facial dysmorphism, and generalised platyspondyly have been encountered. These bone shortenings were associated with bone bending, curving and rhizomelia of the upper limbs with significant macrodactyly. Limitations in articular movements were present. The forearm deformities were similar to those observed in hereditary multiple exostosis.
The acrofrom upper limbs with mixed appearances of radiolucencies, cysts and striae of fibro-chondromatosis are the basic features of type I1Spranger. The constellation of facial dysmorphic features and significant vertebral abnormalities in our present patient were not compatible with the above-mentioned type of enchondromatosis. Our report widens the knowledge of disorders characterised by enchondromatosis. Ascertainment of the mode of inheritance in our present patient was difficult because of insufficient family history and parents declined clinical/radiographic documentation.
PMCID: PMC2600790  PMID: 19017386
23.  Golabi‐Ito‐Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene 
Journal of Medical Genetics  2006;43(6):e30.
Golabi, Ito, and Hall reported a family with X linked mental retardation (XLMR), microcephaly, postnatal growth deficiency, and other anomalies, including atrial septal defect, in 1984.
This family was restudied as part of our ongoing study of XLMR, but significant linkage to X chromosome markers could not be found. Extreme short stature and microcephaly as well as other new clinical findings were observed. Mutations in the polyglutamine tract binding protein 1 gene (PQBP1) have recently been reported in four XLMR disorders (Renpenning, Hamel cerebro‐palato‐cardiac, Sutherland‐Haan, and Porteous syndromes) as well as in several other families. The clinical similarity of our family to these patients with mutations in PQBP1, particularly the presence of microcephaly, short stature, and atrial septal defect, prompted examination of this gene.
A missense mutation in PQBP1 was identified which changed the conserved tyrosine residue in the WW domain at position 65 to a cysteine (p.Y65C).
This is the first missense mutation identified in PQBP1 and the first mutation in the WW domain of the gene. The WW domain has been shown to play an important role in the regulation of transcription by interacting with the PPxY motif found in transcription factors. The p.Y65C mutation may affect the proper functioning of the PQBP1 protein as a transcriptional co‐activator.
PMCID: PMC2564547  PMID: 16740914
Golabi‐Ito‐Hall syndrome; microcephaly;  PQBP1 ; Renpenning syndrome; X linked mental retardation
24.  A new variant of spondylometaphyseal dysplasia with autosomal dominant mode of inheritance. 
Journal of Medical Genetics  1982;19(2):104-109.
Clinical and radiographic evaluation of an infant boy and his father revealed findings suggesting a new variant of spondylometaphyseal dysplasia with an apparently autosomal dominant mode of inheritance. The main clinical findings included short stature and marked ligamentous laxity in the infant. X-ray findings included severe and peculiar multiple metaphyseal involvement and striking vertebral undermineralisation in the infant, and platyspondyly in the father. However, all the epiphyses were normal. Laboratory studies were essentially normal except for an extremely raised serum alkaline phosphatase in the infant. The uniqueness of these findings suggests a new variant of the spondylometaphyseal dysplasias, distinct from the cases described initially by Kozlowski et al and subsequent investigators.
PMCID: PMC1048838  PMID: 7077620
25.  Severe Short Stature: an unusual finding in lipoid proteinosis 
Lipoid proteinosis (LP) is a rare disorder and it can affect every organ in the body. The clinical manifestations of LP may vary considerably between affected individuals. Short stature is reported in patients with LP however the underlying etiology is not clear. Short stature may be due to endocrine dysfunction caused by deposition of hyaline−like material in endocrine glands. We investigated a 13 year old patient with LP (507 delT mutation) who had severe short stature. He had hoarseness since the age of one year, followed by characteristic skin lesions for LP and short stature. There was no pathology with respect to endocrinological investigations in our patient including growth hormone−IGF axis. Our results show that short stature in LP can not be explained by endocrinological abnormalities. Short stature may be an intrinsic component of the syndrome.
Conflict of interest:None declared.
PMCID: PMC3005640  PMID: 21318070
short stature; Genodermatosis; lipoid proteinosis

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