Nicola C. Ho

Structural and Functional Mutations of the Perlecan Gene Cause Schwartz-Jampel Syndrome, with Myotonic Myopathy and Chondrodysplasia

Perlecan, a large heparan sulfate proteoglycan, is a component of the basement membrane and other extracellular matrices and has been implicated in multiple biological functions. Mutations in the perlecan gene (HSPG2) cause two classes of skeletal disorders: the relatively mild Schwartz-Jampel syndrome (SJS) and severe neonatal lethal dyssegmental dysplasia, Silverman-Handmaker type (DDSH). SJS is an autosomal recessive skeletal dysplasia characterized by varying degrees of myotonia and chondrodysplasia, and patients with SJS survive. The molecular mechanism underlying the chondrodystrophic myotonia phenotype of SJS is unknown. In the present report, we identify five different mutations that resulted in various forms of perlecan in three unrelated patients with SJS. Heterozygous mutations in two patients with SJS either produced truncated perlecan that lacked domain V or significantly reduced levels of wild-type perlecan. The third patient had a homozygous 7-kb deletion that resulted in reduced amounts of nearly full-length perlecan. Unlike DDSH, the SJS mutations result in different forms of perlecan in reduced levels that are secreted to the extracellular matrix and are likely partially functional. These findings suggest that perlecan has an important role in neuromuscular function and cartilage formation, and they define the molecular basis involved in the difference in the phenotypic severity between DDSH and SJS.

Conservation of the Caenorhabditis elegans timing gene clk-1 from yeast to human: A gene required for ubiquinone biosynthesis with potential implications for aging

Abstract. Mutations in the Caenorhabditis elegans gene clk-1 have a major effect on slowing development and increasing life span. The Saccharomyces cerevisiae homolog COQ7 encodes a mitochondrial protein involved in ubiquinone biosynthesis and, hence, is required for respiration and gluconeogenesis. In this study, RT-PCR and 5′ RACE were used to isolate both human and mouse clk-1/COQ7 homologs. Human CLK-1 was mapped to Chr 16(p12–13.1) by Radiation Hybrid (RH) and fluorescence in situ hybridization (FISH) methods. The number and location of human CLK1 introns were determined, and the location of introns II and IV are the same as in C. elegans. Northern blot analysis showed that three different isoforms of CLK-1 mRNA are present in several tissues and that the isoforms differ in the amount of expression. The functional equivalence of human CLK-1 to the yeast COQ7 homolog was tested by introducing either a single or multicopy plasmid containing human CLK-1 cDNA into yeast coq7 deletion strains and assaying for growth on a nonfermentable carbon source. The human CLK-1 gene was able to functionally complement yeast coq7 deletion mutants. The protein similarities and the conservation of function of the CLK-1/clk-1/COQ7 gene products suggest a potential link between the production of ubiquinone and aging.

A Skeletal Gene Database

Systematic organization of documented data coupled with ready accessibility is of great value to research. Catalogs and databases are created specifically to meet this purpose. The Skeletal Gene Database evolves as part of the Skeletal Genome Anatomy Project (SGAP), an ongoing multi‐institute collaborative effort, to study the functional genome of bone and other skeletal tissues. The primary objective of the Skeletal Gene Database is to create a contemporary list of skeletal‐related genes, offering the following information for each gene: gene name, protein name, cellular function, disease(s) caused by mutation of the corresponding gene, chromosomal location, LocusLink number, gene size, exon/intron numbers, messenger RNA (mRNA) coding region size, protein size/molecular weight, Online Mendelian Inheritance in Man (OMIM) number of the gene, UniGene assignment, and PubMed reference. The database includes genes already known and published in the literature as well as novel genes not yet characterized but known to be expressed in skeletal tissue. It will be posted on the web for easy access and swift referencing. The data will be updated in tempo with current and future research, thereby providing an invaluable service to the scientific community interested in obtaining information on bone‐related genes.

Mutations of CTSK Result in Pycnodysostosis via a Reduction in Cathepsin K Protein

Pycnodyostosis, an autosomal recessive osteosclerosing skeletal disorder, has recently been shown to result from mutations in the cathepsin K gene. Cathepsin K, a lysosomal cysteine protease with an abundant expression in osteoclasts, has been implicated in osteoclast‐mediated bone resorption and remodeling. DNA sequence analysis of the cathepsin K gene in a nonconsanguineous family demonstrated compound heterozygozity for mutations in two affected siblings. We have identified a missense mutation with a single base G→A transition at cDNA nucleotide 236, resulting in conversion of a conserved glycine to a glutamine residue (G79E). The other mutation is an A→T transition at nucleotide 154, leading to the substitution of a lysine residue by a STOP codon (K52X) predicting premature termination of the precursor cathepsin K polypeptide. Sequencing of genomic and cDNAs from the parents demonstrated that the missense mutation was inherited from the father and the nonsense mutation from the mother. Protein expression in both affected children was virtually absent, while in the parents was reduced by 50–80% compared with controls. The protein studies demonstrate that even significantly reduced cathepsin K levels do not have any phenotypic effect, whereas absent cathepsin K results in pycnodysostosis.

Jeune asphyxiating thoracic dystrophy and short-rib polydactyly type III (Verma-Naumoff) are variants of the same disorder

Jeune syndrome (JS) and short-rib polydactyly syndrome type III (SRP type III) are autosomal recessive disorders characterized by short ribs and polydactyly. They are distinguished from each other by the more severe radiological and histological bone findings as well as the occurrence of facial anomalies, ambiguous genitalia, and occasionally, cloacal abnormalities in SRP type III. We present a family in which two children have mild JS and one has SRP type III as evidence that JS and SRP type III are variants of the same disorder. The intrafamilial variability may reflect the effects of modifying loci on gene expression.

[Marfan's syndrome].

1978 www.thelancet.com Vol 366 December 3, 2005 Marfan’s syndrome is a multisystem connective tissue disorder of autosomal dominant inheritance. Approximately one in every 5000 individuals is affected, though this figure is probably an underestimate. The condition shows no predilection for any particular race or geographical background. It exhibits complete penetrance but variable expression and age dependency. About a quarter of affected individuals have no family history of the disease—ie, they are new mutations. Marfan’s syndrome demonstrates pleiotropy with diverse manifestations in different organ systems. Clinical diagnosis depends on a combination of major and minor signs defined in the revised 1996 Ghent criteria. The hallmark features are noted in the cardiovascular, ocular, and skeletal systems (table). The diagnosis of Marfan’s syndrome can be challenging because of phenotypic variability even between affected individuals of the same family, low specificity of many of the clinical signs, and multiple Marfan-like microfibrillar disorders with overlapping features. The gene for Marfan’s syndrome was localised to chromosome 15q21 in 1990 and cloned in 1991. FBN1 is a huge gene, spanning 110 kb of genomic DNA and comprising 65 exons. It encodes the microfibrillar protein fibrillin 1. Mutational analysis is difficult and impractical at times, in part because of the size of the gene, the heterogeneity of mutations discovered, and the lack of mutational hot spots. Moreover, there are currently no molecular techniques that offer a highly sensitive mutation detection rate of FBN1. Fibrillin 1 is a major component of extracellular microfibrils. It consists of cysteine-rich repeats interspersed by latent transforming growth factor binding protein-like and epidermal growth factor-like motifs. The microfibrils are thought to confer important biomechanical properties in connecting, anchoring, and maintaining tissues and organs. Many mutations associated with fibrillin 1 appear to confer a dominant negative mechanism of pathogenesis, but some associated with fibrillin-1 haploinsufficiency have also been described. These mutations can lead to defects in the synthesis, secretion, modification, folding, stabilisation, incorporation, and assembly of the FBN1 protein. Severe neonatal Marfan’s syndrome is associated with a cluster of mutations in the middle portion of FBN1, but there are no other established correlations between genotype and phenotype. Currently, our understanding of fibrillin biochemistry and microfibrillar assembly is limited. Experiments in mice could provide insight into fibrillin pathogenesis and microfibrillar organisation, leading to a better understanding of the pleiotropic manifestations of Marfan’s syndrome and perhaps development of a cure. Lancet 2005; 366: 1978–81

Living with achondroplasia: quality of life evaluation following cervico-medullary decompression.

Achondroplasia is the most common of the heritable skeletal dysplasias. Cervico‐medullary compression is a frequently encountered and potentially lethal neurological complication. Cervico‐medullary decompression (CMD) at the foramen magnum is often employed to relieve the pressure on the emerging cervical cord. Given the inherent risks associated with major surgery, there has been a substantial debate regarding the best criteria for CMD. Our objectives for this study are to explore the quality of life of patients who had undergone CMD, and to assess whether surgery is associated with mortality and increased long‐term morbidity. A Medical Outcome Study 36‐item Short Form General Health Survey designed to evaluate eight general health concepts as well as achondroplasia‐related issues, was administered to patients assessed in the neurosurgery department in Johns Hopkins Hospital between 1977 and 1998. One hundred and sixty‐seven patients were eligible for inclusion. Forty‐three could not be contacted, and two refused consent. One hundred and twenty‐two patients were assessed. Fifty‐six (46%) individuals had CMD and 66 (54%) did not. There was 1 case of mortality in the CMD group and 12 cases in the non‐CMD group. In the non‐CMD group, all deaths, as far as we know, were unrelated to cervico‐medullary compression. In this cohort of surviving patients (n = 109), the quality of life of the 55 (50.5%) who had undergone CMD is comparable to that of the 54 (49.5%) who did not have surgery, controlled for age and sex. CMD is indicated for patients with achondroplasia with significant symptomatic foramen magnum compression. It can be life saving. It can abolish profound central apnea that may cause sudden death and alleviate neurological complications associated with damage of the significantly compressed spinal cord. With regards to long‐term outcome evaluation, the quality of life of individuals with achondroplasia who had CMD is similar to those age‐ and sex‐matched patients who did not have this surgery. Moreover, CMD, with all its inherent surgical risks, does not appear to be associated with higher mortality or increased long‐term morbidity.

Clinico-pathogenetic findings and management of chondrodystrophic myotonia (Schwartz-Jampel syndrome): a case report

BackgroundChondrodystrophic myotonia or Schwartz-Jampel syndrome is a rare genetic disorder characterized by myotonia and skeletal dysplasia. It may be progressive in nature. Recently, the gene responsible for Schwartz-Jampel syndrome has been found and the defective protein it encodes leads to abnormal cartilage development and anomalous neuromuscular activity.Case PresentationWe report the clinical findings and the management of an 8-year-old boy with this disorder. The molecular findings confirm that the patient is a compound heterozygote with a different splicing mutation in each Perlecan allele. This resulted in a significant reduction in the production of the encoded normal protein.ConclusionWe discuss the multi-disciplinary management of Schwartz-Jampel syndrome that will facilitate optimal care and timely intervention of patients with this disorder.

Famous people and genetic disorders: from monarchs to geniuses--a portrait of their genetic illnesses.

Famous people with genetic disorders have always been a subject of interest because such news feeds the curiosity the public has for celebrities. It gives further insight into their lives and provides a medical basis for any unexplained or idiosyncratic feature or behavior they exhibit. It draws admiration from society of those who excel in their specialized fields despite the impositions of their genetic illnesses and also elicits sympathy even in the most casual observer. Such news certainly catapults a rare genetic disorder into the realm of public awareness. We hereby present six famous figures: King George III, Toulouse‐Lautrec, Queen Victoria, Nicolo Paganini, Abraham Lincoln, and Vincent van Gogh, all of whom made a huge indelible mark in either the history of politics or that of the arts.

Epidermal nevi and localized cranial defects

We report on a girl with a congenital pigmented hairy nevus of the scalp, epidermal nevi of the right temple, and localized cranial defects. We have not found other reported cases of giant pigmented hairy nevus of the scalp occurring with absence of underlying cranial bone. We speculate that the localized cranial defects are undergrowth anomalies representative of a paracrinopathy from the overlying nevus or simultaneous bone/skin dysplasia, the former having been resorbed. In the absence of a familial history of epidermal nevi and/or seizures, our patient represents a sporadic case, perhaps a somatic mutation.