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X-exome capture and sequencing was performed to identify a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the terminal osseous dysplasia (TOD) disease which is an x-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin and recurrent digital fibroma with onset in female infancy. The data obtained revealed that TOD is caused by single recurrent mutation in the FLNA gene.

The article explains the different mutations taking place in the Calcium-Activated Nucleotidase-1 (CANT-1) gene, which are shown to lead to Desbuquois dysplasia. The various symptoms, causes and the effects of the disorder on humans are also explained.

Serotonin synthesis in mammals is initiated by 2 distinct tryptophan hydroxylases (TPH), TPH1 and TPH2. By genetically ablating TPH2, we created mice ([Tph2.sup.-/-]) that lack serotonin in the central nervous system. Surprisingly, these mice can be born and survive until adulthood. However, depletion of serotonin signaling in the brain leads to growth retardation and 50% lethality in the first 4 weeks of postnatal life. Telemetric monitoring revealed more extended daytime sleep, suppressed respiration, altered body temperature control, and decreased blood pressure (BP) and heart rate (HR) during nighttime in [Tph2.sup.-/-] mice. Moreover, [Tph2.sup.-/-] females, despite being fertile and producing milk, exhibit impaired maternal care leading to poor survival of their pups. These data confirm that the majority of central serotonin is generated by TPH2. TPH2-derived serotonin is involved in the regulation of behavior and autonomic pathways but is not essential for adult life. growth retardation | maternal care | respiration | serotonin | sleep

The article studies the first identification of pathogenic sequence variants in OBSL1, a cytoskeletal adaptor protein, causing the primordial growth disorder 3-M syndrome. Findings reveal that the loss of OBSL1 leads to downregulation of CUL7 gene.

Dyggve--Melchior--Clausen syndrome and Smith-McCort dysplasia are recessive spondyloepimetaphyseal dysplasias caused by loss-of-function mutations in dymeclin (Dym), a gene with previously unknown function. Here we report that Dym-deficient mice display defects in endochondral bone formation similar to that of Dyggve--Melchior--Clausen syndrome and Smith-McCort dysplasia, demonstrating functional conservation between the two species. Dym-mutant cells display multiple defects in vesicle traffic, as evidenced by enhanced dispersal of Golgi markers in interphase cells, delayed Golgi reassembly after brefeldin A treatment, delayed retrograde traffic of an endoplasmic reticulum-targeted Shiga toxin B subunit, and altered furin trafficking; and the Dym protein associates with multiple cellular proteins involved in vesicular traffic. These results establish dymeclin as a novel protein involved in Golgi organization and intracellular vesicle traffic and clarify the molecular basis for chondrodysplasia in mice and men. bone formation | gene trap mutation | Golgi | proteomics | growth plate

The interest of the approach by mapping a gene for Taybi-Linder syndrome to chromosome 2q is shown with the use of a key patient with no genealogical information. This could be achieved by estimating inbreeding coefficients from the patients' genomic information and using these estimates to perform homozygosity mapping.

Background. Delayed growth is a well-established feature of pediatric Crohn's disease. Several factors have been shown to affect growth, including disease location, severity, and treatment. The recently discovered NOD2 gene has been correlated to ileal location of Crohn's disease and subsequently could affect growth through the resulting phenotype or as an independent risk factor. The aim of our study was to determine if growth retardation is affected by genotype independently of disease location or severity. Methods. Genotyping for 3 NOD2 single-nucleotide polymorphisms was performed in 93 patients with detailed growth records. Parameters including disease location, disease severity, and NOD 2 genotype and their effect on z scores for height and weight at disease onset and during follow-up were analyzed. Results. NOD2 mutations were correlated with ileal location but not with disease severity or growth retardation. Ileal involvement was significantly associated with height retardation at disease onset and the lowest z score during follow-up. Use of steroids affected weight but not height. Regression models for growth variables revealed that the strongest association with impaired growth is with disease severity (weight- and height-failure odds ratios: 6.17 and 4.52, respectively). Conclusions. Severity of disease is correlated with growth failure for both height and weight. Location of disease is a weaker predictor of disordered growth and is correlated with growth retardation but not growth failure. The NOD2 genotype was not correlated with growth retardation or growth failure. Pediatrics 2004;114:1281-1286; NOD2, height failure, weight failure, Crohn's disease, growth, inflammatory bowel disease, genes, pediatric., ABBREVIATIONS. CD, Crohn's disease; SNP, single-nucleotide polymorphism; PCR, polymerase chain reaction; OR, odds ratio; CI, 95% confidence interval Growth retardation is a frequent feature of pediatric Crohn's disease (CD). Up [...]

The dwarfing alleles in wheat (Triticum aestivum L.) are associated with shorter coleoptile length that can produce unacceptable and erratic stands. The combined effect of temperature (2, 10, 18°C) and five gibberellic acid (GA) concentrations [0, 5, 50, 100, 500 mg [L.sup.-1] of potassium gibberellin [A.sub.3] ([C.sub.19][H.sub.21][O.sub.6]K)] in the germination medium on the coleoptile length of four homozygous isolines [normal or T-0 (Rht-B1a/Rht-D1a), semidwarf-1 or SD-1 (Rht-B1b/Rht-D1a), semidwarf-2 or SD-2 (Rht-B1a/Rht-D1b), dwarf or D-12 (Rht-B1b/Rht-D1b)] in `Marfed' (spring) and `Burr' (winter) was studied. With each decrease in temperature, the coleoptile length in each isoline and cultivar increased, with the increase greater in those isolines and cultivars having the shortest length at 18°C and containing at least one dwarfing allele (Rht-B1b and/or Rht-D1b). At 2°C, higher GA concentrations increased coleoptile length over 0 GA mg [L.sup.-1] in all isolines, with the greatest increase at the 500 mg [L.sup.-1] concentration. The three midconcentrations (5, 50, 100 mg [L.sup.-1]) resulted in an intermediate but almost equal increase. Increasing temperatures decreased the response to GA so that at 18°C, only T-0 and SD-1 responded to GA applications. The reported 'GA insensitivity' was found to be highly temperature dependent, with the Rht-B1b allele having a wider temperature response range than Rht-D1b. The results suggested that differences in genetic background, possibly related to the winter-spring growth habit, could influence the effect of the dwarfing alleles., GENETIC DWARFING IN WHEAT influences many seed, seedling, and plant characteristics (Gale and Youssefian, 1985). Dwarf genotypes carrying the dwarfing Rht-B1b and/or Rht-D1b alleles (McIntosh, 1988; Borner et al., 1996) [...]

Chondrodysplastic dwarfism in Japanese brown cattle is an autosomal recessive disorder characterized by short limbs. Previously, we mapped the locus responsible for the disease on the distal end of bovine chromosome 6. Here, we narrowed the critical region to [approximately equal to] 2 cM by using linkage analysis, constructed a BAC and YAC contig covering this region, and identified a gene, LIMBIN (LBN), that possessed disease-specific mutations in the affected calves. One mutation was a single nucleotide substitution leading to an activation of a cryptic splicing donor site and the other was a one-base deletion resulting in a frameshift mutation. Strong expression of the Lbn gene was observed in limb buds of developing mouse embryos and in proliferating chondrocytes and bone-forming osteoblasts in long bones. These findings indicate that LBN is responsible for bovine chondrodysplastic dwarfism and has a critical role in a skeletal development.

The subtilisin-like proprotein convertases PC1/3 (SPC3) and PC2 (SPC2) are believed to be the major endoproteolytic processing enzymes of the regulated secretory pathway. They are expressed together or separately in neuroendocrine cells throughout the brain and dispersed endocrine system in both vertebrates and invertebrates. Disruption of the gene-encoding mouse PC1/3 has now been accomplished and results in a syndrome of severe postnatal growth impairment and multiple defects in processing many hormone precursors, including hypothalamic growth hormone-releasing hormone (GHRH), pituitary proopiomelanocortin to adrenocorticotropic hormone, islet proinsulin to insulin and intestinal proglucagon to glucagon-like peptide-1 and -2. Mice lacking PC1/3 are normal at birth, but fail to grow normally and are about 60% of normal size at 10 weeks. They lack mature GHRH, have low pituitary growth hormone (GH) and hepatic insulin-like growth factor-1 mRNA levels and resemble phenotypically the 'little' mouse (Gaylinn, B. D., Dealmeida, V. I., Lyons, C. E., Jr., Wu, K. C., Mayo, K. E. & Thorner, M. O. (1999) Endocrinology 140, 5066-5074) that has a mutant GHRH receptor. Despite a severe defect in pituitary proopiomelanocortin processing to mature adrenocorticotropic hormone, blood corticosterone levels are essentially normal. There is marked hyperproinsulinemia but without impairment of glucose tolerance. In contrast, PC2-null mice lack mature glucagon and are chronically hypoglycemic (Furuta, M., Yano, H., Zhou, A., Rouille, Y., Hoist, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H. & Steiner, D. (1997) Proc Natl. Acad. Sci. USA 94, 6646-6651). The PC1/3-null mice differ from a human subject reported with compound heterozygosity for defects in this gene, who was of normal stature but markedly obese from early life. The PC1/3-null mice are not obese. The basis for these phenotypic differences is an interesting topic for further study. These findings prove the importance of PC1/3 as a key neuroendocrine convertase.

Mutations in the thyroid hormone receptor [beta] (TR[beta]) gene result in resistance to thyroid hormone. However, it is unknown whether mutations in the TR[alpha] gene could lead to a similar disease. To address this question, we prepared mutant mice by targeting mutant thyroid hormone receptor kindred PV (PV) mutation to the TR[alpha] gene locus by means of homologous recombination (TR[alpha]1PV mice). The PV mutation was derived from a patient with severe resistance to thyroid hormone that has a frameshift of the C-terminal 14 aa of TR[beta]1. We knocked in the same PV mutation to the corresponding TR[alpha] gene locus to compare the phenotypes of TR[alpha][1.sup.PV/+] mice with those of TR[[beta].sup.PV/+] mice. TR[alpha][1.sup.PV/+] mice were viable, indicating that the mutation of the TR[alpha] gene is not embryonic lethal. In drastic contrast to the TR[[beta].sup.PV/+] mice, which do not exhibit a growth abnormality, TR[alpha][1.sup.PV/+] mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to TR[[beta].sup.PV/+] mice, which have a hyperactive thyroid, TR[alpha][1.sup.PV/+] mice exhibited mild thyroid failure. The in vivo pattern of abnormal regulation of T3 target genes in TR[alpha][1.sup.PV/+] mice was unique from those of TR[[beta].sup.PV/+] mice. The distinct phenotypes exhibited by TR[alpha][1.sup.PV/+] and TR[[beta].sup.PV/+] mice indicate that the in vivo functions of TR mutants are isoform-dependent. The TR[alpha][1.sup.PV/+] mice may be used as a tool to uncover human diseases associated with mutations in the TR[alpha] gene and, furthermore, to understand the molecular mechanisms by which TR isoforms exert their biological activities.

FGF signaling, FGFs being a large family of fibroblast growth factors, regulates bone development through the STAT-1 pathway and inhibits chrondrocyte proliferation. Several genetic forms of human dwarfism have been linked to activating mutations in FGF receptor 3, indicating that FGF signaling has a vital role in chondrocyte maturation and development of the skeleton. The mechanisms by which FGFs affect chondrocyte proliferation and differentiation are not well understood. Activation of FGF signaling cuts down chondrocyte proliferation in a rat chondrosarcoma cell line and in primary murine chondrocytes. Primary chondrocytes from STAT-1 knock-out mice have been used to give genetic evidence that STAT-1 function is needed for the FGF mediated growth inhibition. It seems STAT-1 mediated downregulation of chondrocyte proliferation by FGF signaling is a homeostatic mechanism that ensures harmonious bone morphogenesis and development.

Byline: Sonya Rae Arnold (1), Diane Spicer (3), Boris Kouseff (4), Atilano Lacson (1), Enid Gilbert-Barness (1) Keywords: Key words: Seckel syndrome, bird-headed dwarfism, autosomal recessive, mental retardation, microcephaly, skeletal abnormalities Abstract: Seckel syndrome has been described as the prototype of the primordial bird-headed type of dwarfism. Since Seckel originally defined the disorder, less than 60 cases have been reported. In addition to the characteristic craniofacial dysmorphism and skeletal defects, abnormalities have been described in the cardiovascular, hematopoietic, endocrine, and central nervous systems. This pleiotropy has implied genetic heterogeneity and prompted reviews of previously reported cases of Seckel syndrome. As a result, the characteristic diagnostic features of Seckel syndrome have been highly debated. Although deletions in chromosome 2q have been described, to date, no genetic defect has been defined. We report three cases of Seckel-like syndrome in siblings from nonconsanguinous Caucasian parents. In addition to the typical Seckel phenotypic features, all three cases were characterized by severe hydrocephalus. We review the literature and propose that there is a spectrum of Seckel conditions that share some common key features, but also demonstrate a wide range of phenotypic features. Author Affiliation: (1) Department of Pathology, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, MDC 11, Tampa, FL 33612-4742, USA , US (2) Department of Pathology, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213-5283, USA , US (3) Department of Pathology, Tampa General Hospital, P.O. Box 1289, Tampa, FL 33601-1289, USA , US (4) Department of Pediatrics, Division of Genetics, University of South Florida, 10770 North 46th Street, Suite C-900, Tampa, FL 33617-3451, USA , US (5) Department of Pathology, All Children's Hospital, 801 Sixth Street South, P.O. Box 31020, Department 7020, St. Petersburg, FL 33731-8920, USA , US Article note: Received February 3, 1998 accepted July 6, 1998.

In a systematic screen for maternally expressed imprinted genes using subtraction hybridization with androgenetic and normal fertilized mouse embryos, seven candidate maternally expressed genes (Megs) have been isolated, including the H19 and [p57.sup.Kip2] genes that are known to be maternally expressed. Herein, we demonstrate that an imprinted gene, Meg1, is apparently identical to Grb10 (growth factor receptor-bound protein 10), which is located on mouse proximal chromosome 11. Grb10 protein was reported to bind to the insulin receptor and/or the insulin-like growth factor (IGF) I receptor via its src homology 2 domain and to inhibit the associated tyrosine kinase activity that is involved in the growth promoting activities of insulin and IGFs (IGF-I and -II). Thus, it is probable that Meg1/Grb10 is responsible for the imprinted effects of prenatal growth retardation or growth promotion caused by maternal or paternal duplication of proximal chromosome 11 with reciprocal deficiencies (MatDp.prox11 or PatDp.prox11), respectively. In the human, it has been reported that the maternal uniparental disomy 7 is responsible for the Silver-Russell syndrome (SRS) whose effects include pre- and postnatal growth retardation and other dysmorphologies. The human homologue GRB10 on chromosome 7q11.2-12 is a candidate gene for Silver-Russell syndrome.

Mutations in the gene for cartilage oligomeric matrix protein (COMP) bring some forms of multiple epiphyseal dysplasia (MED) and bring pseudoachondroplasia (PSACH). Early-onset osteoarthrosis and mild-to-severe short-limb dwarfism occur with PSACH and MED. In 14 families with MED or PSACH phenotypes COMP mutations have been identified. In the region of the COMP gene that encodes the calmodulin-like repeat elements mutations thought likely to bring with them single amino acid deletions/substitution have been found in people with moderate to sever PSACH. In the same domain a missense mutation that brought MED Fairbank was found. It appears that there is phenotype overlap for MED and PSACH. The carboxyl-terminal domain is a factor in the structure and /or function of COMP.

The major gibberellin (GA) controlling stem elongation in pea (Pisum sativum L.) is G[A.sub.1], which is formed from G[A.sub.20] by 3[Beta]-hydroxylation. This step, which limits G[A.sub.1] biosynthesis in pea, is controlled by the Le locus, one of the original Mendelian loci. Mutations in this locus result in dwarfism. We have isolated cDNAs encoding a GA 3[Beta]-hydroxylase from lines of pea carrying the Le, le, le-3, and [le.sup.d] alleles. The cDNA sequences from le and le-3 each contain a base substitution resulting in single amino acid changes relative to the sequence from Le. The cDNA sequence from [le.sup.d], a mutant derived from an le line, contains both the le 'mutation' and a single-base deletion, which causes a shift in reading frame and presumably a null mutation. cDNAs from each line were expressed in Escherichia coli. The expression product for the clone from Le converted G[A.sub.9] to G[A.sub.4], and G[A.sub.20] to G[A.sub.1], with gm values of 1.5 [[micro]molar] and 13 [[micro]molar], respectively. The amino acid substitution in the clone from le increased [K.sub.m] for G[A.sub.9] 100-fold and reduced conversion of G[A.sub.20] to almost nil. Expression products from le and le-3 possessed similar levels of 3[Beta]-hydroxylase activity, and the expression product from [le.sup.d] was inactive. Our results suggest that the 3[Beta]-hydroxylase cDNA is encoded by Le. Le transcript is expressed in roots, shoots, and cotyledons of germinating pea seedlings, in inter-nodes and leaves of established seedlings, and in developing seeds.

Mouse cartilage matrix deficiency (cmd) is an autosomal recessive disorder caused by a genetic defect of aggrecan, a large chondroitin sulfate proteoglycan in cartilage. The homozygotes (-/-) are characterized by cleft palate and short limbs, tail, and snout. They die just after birth because of respiratory failure, and the heterozygotes (+/-) appear normal at birth. Here we report that the heterozygotes show dwarfism and develop spinal misalignment with age. Within 19 months of age, they exhibit spastic gait caused by misalignment of the cervical spine and die because of starvation. Histological examination revealed a high incidence of herniation and degeneration of vertebral discs. Electron microscopy showed a degeneration of disc chondrocytes in the heterozygotes. These findings may facilitate the identification of mutations in humans predisposed to spinal degeneration.

The two most commonly used dwarfing genes of bread wheat (Triticum aestivum L.) are Rht1 and Rht2. The Rht3 gene is also a potent dwarfing gene. Information in the literature is limited as to the comparative effects of these genes on transpiration efficiency (TE) and water-use efficiency (WUE). Carbon isotope discrimination [Delta] has been proposed as a criterion to select for improved TE. Four near-isogenic lines, rhtrht, Rht1Rht1, Rht2Rht2, and Rht3Rht3, in 'Maringa' bread wheat background and four of their near-isogenic [F.sub.1] hybrids derived from crossing the original lines were used to determine the effects of dwarfing genes on plant height, root dry matter, shoot dry matter including grains, grain yield, total dry matter (TDM), TE (TDM/water transpired), WUE (grain yield/water used), and [Delta] in well-watered and droughted pot experiments in the glasshouse. The near-isogenic lines and their six [F.sub.1] hybrids were also grown in well-watered and droughted field conditions. Plant height ranged from 60 to 124 cm and from 53 to 121 cm in well-watered and droughted pot experiments, and it varied from 50 to 94 cm and from 49 to 90 cm in well-watered and droughted field experiments, respectively. Total dry matter, grain yield, TE, and WUE declined with plant height in well-watered glasshouse conditions. No significant relationships were found between plant height and these traits in droughted glasshouse conditions. Carbon isotope discrimination was negatively correlated with TE, but significantly so only in the well-watered pot experiment. Plant height was negatively associated with [Delta] in both well-watered and droughted pot and field experiments. Grain yield and shoot dry matter also declined with plant height in field conditions. Negative correlations were observed between [Delta] and grain yield and [Delta] and shoot dry matter in well-watered field conditions. In most cases, the dwarfing genes reduced shoot dry matter more than grain yield and, therefore, harvest index of the semidwarf and dwarf lines was higher than that of the tall standard line. The dwarfism caused by Rht1, Rht2, and Rht3 genes had, in general, depressing effects on TE, WUE, TDM, and grain yield.

Genetic mutations in cytokine receptors may cause several congenital blood production diseases. Cytokine receptors are found on blood precursor cells and are receptors for blood-forming growth factors. Familial erythrocytosis, or the benign overproduction of red blood cells, may be caused by a nonsense mutation in the gene responsible for producing the erythropoietin hormone receptor. Nonsense mutations may also cause Kostmann's syndrome, a disease in which white blood cells do not mature, leading to a reduction in the number of white blood cells. Interleukin-2 receptor mutations have been associated with X-linked severe combined immunodeficiency, a disease characterized by immune system dysfunction with normal or increased B immune cell numbers, decreased T immune cell production and severe infections. Though the growth hormone receptor is not usually found on blood-forming cells, it does function in the blood production process. Mutations in this receptor may lead to Laron dwarfism and resistance to growth hormone.

Growth retardation and postnatal mortality accompanies embryogenesis in bcl-2-l-mice characterized by the absence of the oncogene, bcl-2. Polycystic kidney disease, fulminant apoptosis of the thymus and spleen and cell death in thymocytes commonly prevail in the bcl-2-l-mice. Programmed cell death is ascribed to the function of oxygen-induced free radicals. Bcl-2 is characterized by a death repressor molecular activity which proceeds through an antioxidant pathway.

Investigators in Israel have previously defined a class of dwarfism that is caused by a defect in cell receptors for growth hormone. Receptors are the specialized biochemical structures found on the surface membranes of cells that bind with the hormone and induce its effect. Laron-type dwarfism (named for the researcher who described it) is identified in patients with small faces, depressed bridge of the nose, small jaws, and large heads; it occurs with equal frequency in males and females. The patients have defects of the hair and teeth, small hands and feet, and frequently have mental retardation. Similar reports of such patients have come from many parts of the world. The present report describes a group of 20 new patients living in Ecuador with a condition similar to Laron-type dwarfism, but they were noticeably distinct with regard to several features. These patients were short in stature, had blue scleras (the 'whites' of the eyes appeared blue), and were usually female; none were intellectually retarded. These individuals were strongly interrelated, of Mediterranean origin (as are the Laron patients), and there was evidence of fetal death of males. Measurement of circulating growth hormone receptor molecules is thought to be indicative of a relative lack of cell-surface growth hormone-binding protein, which in turn results in a decreased ability of growth hormone to produce its effect. These patients had serum levels of growth hormone-binding protein that were only 1 to 30 percent of normal levels. This report is the first concerning a new type of dwarfism caused by a deficit in the quantity of growth hormone-binding protein, and related to the early fetal death of most affected males. (Consumer Summary produced by Reliance Medical Information, Inc.)

A single heterozygous nucleotide exchange in exon M2 of the gene encoding the parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP) receptor was identified in a patient with Jansen-type metaphyseal chondrodysplasia, which changes a strictly conserved histidine residue at position 223 in the receptor's first intracellular loop to arginine. Constitutive, ligand-independent adenosine 3',5'-monophosphate accumulation was observed in COS-7 cells expressing the mutant PTH-PTHrP receptor but not in cells expressing the wild-type receptor. This finding explains the severe ligand-independent hypercalcemia and hypophosphatemia, and most likely the abnormal formation of endochondral bone, in this rare form of short-limbed dwarfism., Jansen-type metaphyseal chondrodysplasia (JMC) [1], a rare form of short-limbed dwarfism, is associated with asymptomatic but often profound hypercalcemia and hypophosphatemia [2, 3], despite the lack of parathyroid gland abnormalities [...]

The skeletal phenotypes of the short-limbed dwarfism (SLW) mouse were examined and chromosomal localization was determined to identify the gene responsible for the phenotypes. It was seen that the disturbed endochondral ossification and a mutation in the Npr2 gene was responsible for the phenotypes of the SLW mouse that caused dwarf phenotype.

The article analyzes adaptationist and biomedical interpretations of growth perturbation and small size which are commonly applied in biology.