Musculoskeletal Phenotypes Research Articles

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Mutations: a Potential Common Cause of Alzheimer's Disease and Musculoskeletal Disorders

Alzheimer's disease (AD), a worldwide growing health issue, is a purely neurodegenerative form of age‐induced dementia. Interestingly, weight loss is frequently associated with disease severity and clinical progression and has been shown to begin at least ten years before the diagnosis of the disease. Bone frailty and sarcopenia have each also been linked to the onset of this disease, although very little is known about the pathogenesis of these conditions in subjects with AD. Indeed, although a common link between dementia and osteoporosis has been suggested, it has never been conclusively demonstrated. The prevalence of both conditions increase with aging, and some genetic conditions can lead to both AD and osteoporosis. Examples for the potential common cause of the 2 conditions are mutations of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene, primarily expressed in myeloid cells or microglia in brain and in osteoclasts in bone, which result in AD and dementia, as well as in bone fragility. In a recent Genome Wide Association Study, a single nucleotide polymorphism (SNP) encoding the R47H variant in TREM2 was linked with strong single allele genetic risk factors for AD, as well as with increased risk for Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. In addition, recent studies showed that mice expressing the R47H TREM2 variant exhibit loss of TREM2 function and neuritic dystrophy. In a similar manner, another TREM2 mutation, the Y38C variant, was previously described in the pathogenesis of Nasu‐Hakola disease (also known as PLOSL) which is characterized by extensive white matter loss and frontotemporal‐like dementia and polycystic lipomembranous osteodysplasia. To investigate whether mutations in the TREM2 gene, previously associated with AD and frontotemporal dementia, also affect the skeleton, we analyzed the musculoskeletal phenotype of mice in which the Y38C and R47H variants of the TREM2 gene are ubiquitously expressed, generated by Drs. Lamb and Landreth at the Stark Neuroscience Research Institute, Indiana University School of Medicine. Our studies showed decreased bone mass in mice expressing the TREM2 mutants at 6–8 months of age. Interestingly, even though TREM2 expression was absent in skeletal muscle of wild type mice, mice expressing the R47H TREM2 variant exhibit decrease muscle mass. In summary, our results suggest a common cause of cognitive disorders and bone loss, and support an indirect role of TREM2 mutations on the loss of muscle mass, secondary to the altered bone remodeling.Support or Funding InformationNIH/NIAMS R01AR067210ICMH Collaborative Pilot Project AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Masticatory Apparatus Performance and Functional Morphology in the Extremely Large Mice from Gough Island.

Since their arrival approximately 200 years ago, the house mice (Mus musculus) on Gough Island (GI) rapidly increased in size to become the largest wild house mice on record. Along with this extreme increase in body size, GI mice adopted a predatory diet, consuming significant quantities of seabird chicks and eggs. We studied this natural experiment to determine how evolution of extreme size and a novel diet impacted masticatory apparatus performance and functional morphology in these mice. We measured maximum bite force and jaw opening (i.e., gape) along with several musculoskeletal dimensions functionally linked to these performance measurements to test the hypotheses that GI mice evolved larger bite forces and jaw gapes as part of their extreme increase in size and/or novel diet. GI mice can bite more forcefully and open their jaws wider than a representative mainland strain of house mice. Similarly, GI mice have musculoskeletal features of the masticatory apparatus that are absolutely larger than WSB mice. However, when considered relative to body size or jaw length, as a relevant mechanical standard, GI mice show reduced performance, suggesting a size-related decrease in these abilities. Correspondingly, most musculoskeletal features are not relatively larger in GI mice. Incisor biting leverage and condylar dimensions are exceptions, suggesting relative increases in biting efficiency and condylar rotation in GI mice. Based on these results, we hypothesize that evolutionary enhancements in masticatory performance are correlated with the extreme increase in body size and associated musculoskeletal phenotypes in Gough Island mice. Anat Rec, 2019. © 2018 American Association for Anatomy.

Critical Roles of E2F3 in Growth and Musculo-skeletal Phenotype in Mice

E2F3, a member of the E2F family, plays a critical role in cell cycle and proliferation by targeting downstream, retinoblastoma (RB) a tumor suppressor family protein. The purpose of this study, was to investigate the role and function of E2F3 in vivo. We examined phenotypic abnormalities, by deletion of the E2f3 gene in mice. Complete ablation of the E2F3 was fully penetrant, in the pure C57BL/6N background. The E2f3+/- mouse embryo developed normally without fatal disorder. However, they exhibited reduced body weight, growth retardation, skeletal imperfection, and poor grip strength ability. Findings suggest that E2F3 has a pivotal role in muscle and bone development, and affect normal mouse growth.

Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden

The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69–81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.

Treatment of Enthesitis, Dactylitis and Nail Lesions in Psoriatic Arthritis

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with the skin disease, psoriasis. It is a highly heterogeneous disorder, not only in the musculoskeletal phenotype but also in its cutaneous manifestations. Enthesitis, dactylitis, and nail changes are the hallmark of the disease, and experts in the field believe that the initiating process of PsA is a deep Koebner phenomenon which triggers enthesitis and the subsequent disease process and progression. We aim to discuss the most recent advances in the treatment of enthesitis, dactylitis, and nail changes in psoriatic arthritis. Various treatment regimens have been used to control the above manifestations of PsA, including conventional synthetic disease-modifying agents (csDMARDs), biologic disease-modifying agents (bDMARDs), and newer therapies which include interleukin (IL)-12/23 antagonist (ustekinumab), IL-17 antagonists (secukinumab and ixekizumab), as well as small molecules including the Janus kinase (JAK) inhibitors and phosphodiesterase-4 inhibitor (apremilast). The csDMARDs include methotrexate, sulphasalazine, leflunomide, as well as cyclosporine. These modalities of treatment are further discussed in this review. Rapid escalation of therapy in patients who have an inadequate response to conventional therapy results in better outcomes. Future research includes specific antibodies against the p19 subunit of IL-23.

Replication and discovery of musculoskeletal QTLs in LG/J and SM/J advanced intercross lines.

The genetics underlying variation in health‐related musculoskeletal phenotypes can be investigated in a mouse model. Quantitative trait loci (QTLs) affecting musculoskeletal traits in the LG/J and SM/J strain lineage remain to be refined and corroborated. The aim of this study was to map muscle and bone traits in males (n = 506) of the 50th filial generation of advanced intercross lines (LG/SM AIL) derived from the two strains. Genetic contribution to variation in all musculoskeletal traits was confirmed; the SNP heritability of muscle mass ranged between 0.46 and 0.56; and the SNP heritability of tibia length was 0.40. We used two analytical software, GEMMA and QTLRel, to map the underlying QTLs. GEMMA required substantially less computation and recovered all the QTLs identified by QTLRel. Seven significant QTLs were identified for muscle weight (Chr 1, 7, 11, 12, 13, 15, and 16), and two for tibia length, (Chr 1 and 13). Each QTL explained 4–5% of phenotypic variation. One muscle and both bone loci replicated previous findings; the remaining six were novel. Positional candidates for the replicated QTLs were prioritized based on in silico analyses and gene expression in muscle tissue. In summary, we replicated existing QTLs and identified novel QTLs affecting muscle weight, and replicated bone length QTLs in LG/SM AIL males. Heritability estimates substantially exceed the cumulative effect of the QTLs, hence a richer genetic architecture contributing to muscle and bone variability could be uncovered with a larger sample size.

A detailed musculoskeletal study of a fetus with anencephaly and spina bifida (craniorachischisis), and comparison with other cases of human congenital malformations.

Few descriptions of the musculoskeletal system of humans with anencephaly or spina bifida exist in the literature. Even less is published about individuals in which both phenomena occur together, i.e. about craniorachischisis. Here we provide a detailed report on the musculoskeletal structures of a fetus with craniorachischisis, as well as comparisons with the few descriptions for anencephaly and with musculoskeletal anomalies found in other congenital malformations. We focused in particular on the comparison with trisomies 13, 18, and 21 because neural tube defects have been associated with such chromosomal defects. Our results showed that many of the defects found in the fetus with craniorachischisis are similar not only to anomalies previously described in the available works on musculoskeletal phenotypes seen in fetuses with anencephaly and spina bifida, but also to a wide range of other different conditions/syndromes including trisomies 13, 18 and 21, and cyclopia. The fact that similar anomalies are seen commonly not only in a wide range of different syndromes, but also as variants of the normal human population and as the 'normal' phenotype of other animals, supports Pere Alberch's unfortunately named idea of a 'logic of monsters'. That is, it supports the idea that development is so constrained that both in 'normal' and abnormal development one sees certain outcomes being produced again and again because ontogenetic constraints only allow a few possible outcomes, thus also leading to cases where the anatomical defects of some organisms are similar to the 'normal' phenotype of other organisms. In fact, this applies not only to specific anomalies but also to general patterns, such as the fact that in pathological conditions affecting different regions of the body, one consistently sees more defects on the upper limbs than on the lower limbs. Such general patterns are, again, seen in the fetus examined for this study, which had 29 muscle anomalies on the right upper limb and 22 muscle anomalies on the left upper limb, vs. seven muscle anomalies on the right lower limb and two on the left lower limb. It is therefore hoped that this work, which is part of our effort to describe and compile information on human musculoskeletal defects found in a wide range of conditions, will contribute not only to a better understanding of craniorachischisis in particular and of human congenital malformations in general, but also to broader discussions on the fields of comparative anatomy, and developmental and evolutionary biology.

Refining patterns of joint hypermobility, habitus, and orthopedic traits in joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type.

Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two overlapping heritable disorders (JHS/EDS-HT) recognized by separated sets of diagnostic criteria and still lack a confirmatory test. This descriptive research was aimed at better characterizing the clinical phenotype of JHS/EDS-HT with focus on available diagnostic criteria, and in order to propose novel features and assessment strategies. One hundred and eighty-nine (163 females, 26 males; age: 2-73 years) patients from two Italian reference centers were investigated for Beighton score, range of motion in 21 additional joints, rate and sites of dislocations and sprains, recurrent soft-tissue injuries, tendon and muscle ruptures, body mass index, arm span/height ratio, wrist and thumb signs, and 12 additional orthopedic features. Rough rates were compared by age, sex, and handedness with a series of parametric and non-parametric tools. Multiple correspondence analysis was carried out for possible co-segregations of features. Beighton score and hypermobility at other joints were influenced by age at diagnosis. Rate and sites of joint instability complications did not vary according to age at diagnosis except for soft-tissue injuries. No major difference was registered by sex and dominant versus non-dominant body side. At multiple correspondence analysis, selected features tend to co-segregate in a dichotomous distribution. Dolichostenomelia and arachnodactyly segregated independently. This study pointed out a more protean musculoskeletal phenotype than previously considered according to available diagnostic criteria for JHS/EDS-HT. Our findings corroborated the need for a re-thinking of JHS/EDS-HT on clinical grounds in order to find better therapeutic and research strategies. © 2017 Wiley Periodicals, Inc.

Definitions of Sarcopenia: Associations with Previous Falls and Fracture in a Population Sample.

Sarcopenia is common in later life and may be associated with adverse health outcomes such as disability, falls and fracture. There is no consensus definition for its diagnosis although diagnostic algorithms have been proposed by the European Working Group for Sarcopenia in Older People (EWGSOP), the International Working Group on Sarcopenia (IWGS) and the Foundation for the National Institutes of Health Sarcopenia Project (FNIH). More recently, Binkley and colleagues devised a score-based system for the diagnosis of "dysmobility syndrome" in an attempt to combine adverse musculoskeletal phenotypes, including sarcopenia and osteoporosis, in order to identify older individuals at particular risk. We applied these criteria to participants from the Hertfordshire Cohort Study to define their prevalence in an unselected cohort of UK community-dwelling older adults and assess their relationships with previous falls and fracture. Body composition and areal bone mineral density were measured using dual-energy X-ray absorptiometry, gait speed was determined by a 3-m walk test and grip strength was assessed with a Jamar hand-held dynamometer. Researcher-administered questionnaires were completed detailing falls and fracture history. The prevalence of sarcopenia in this cohort was 3.3, 8.3 and 2.0% using the EWGSOP, IWGS and related definition of FNIH, respectively; 24.8% of individuals had dysmobility syndrome. Individuals with dysmobility reported significantly higher number of falls (last year and since the age of 45 years) (p < 0.01) than those without it, but no increased fracture rate was observed in this group (p = 0.96). Those with sarcopenia as defined by the IWGS reported significantly higher falls in the last year and prevalent fractures (falls in the last year: OR 2.51; CI 1.09-5.81; p = 0.03; fractures OR 2.50; CI 1.05-5.92; p = 0.04) but these significant associations were not seen when the EWGSOP definition was applied. The IWGS definition of sarcopenia appears to be an effective means of identifying individuals at risk of prevalent adverse musculoskeletal events.

Post-translationally Abnormal Collagens of Prolyl 3-Hydroxylase-2 Null Mice Offer a Pathobiological Mechanism for the High Myopia Linked to Human LEPREL1 Mutations

Myopia, the leading cause of visual impairment worldwide, results from an increase in the axial length of the eyeball. Mutations in LEPREL1, the gene encoding prolyl 3-hydroxylase-2 (P3H2), have recently been identified in individuals with recessively inherited nonsyndromic severe myopia. P3H2 is a member of a family of genes that includes three isoenzymes of prolyl 3-hydroxylase (P3H), P3H1, P3H2, and P3H3. Fundamentally, it is understood that P3H1 is responsible for converting proline to 3-hydroxyproline. This limited additional knowledge also suggests that each isoenzyme has evolved different collagen sequence-preferred substrate specificities. In this study, differences in prolyl 3-hydroxylation were screened in eye tissues from P3h2-null (P3h2(n/n)) and wild-type mice to seek tissue-specific effects due the lack of P3H2 activity on post-translational collagen chemistry that could explain myopia. The mice were viable and had no gross musculoskeletal phenotypes. Tissues from sclera and cornea (type I collagen) and lens capsule (type IV collagen) were dissected from mouse eyes, and multiple sites of prolyl 3-hydroxylation were identified by mass spectrometry. The level of prolyl 3-hydroxylation at multiple substrate sites from type I collagen chains was high in sclera, similar to tendon. Almost every known site of prolyl 3-hydroxylation in types I and IV collagen from P3h2(n/n) mouse eye tissues was significantly under-hydroxylated compared with their wild-type littermates. We conclude that altered collagen prolyl 3-hydroxylation is caused by loss of P3H2. We hypothesize that this leads to structural abnormalities in multiple eye tissues, but particularly sclera, causing progressive myopia.

Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis.

Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype.

Musculoskeletal integration at the wrist underlies the modular development of limb tendons.

The long tendons of the limb extend from muscles that reside in the zeugopod (arm/leg) to their skeletal insertions in the autopod (paw). How these connections are established along the length of the limb remains unknown. Here, we show that mouse limb tendons are formed in modular units that combine to form a functional contiguous structure; in muscle-less limbs, tendons develop in the autopod but do not extend into the zeugopod, and in the absence of limb cartilage the zeugopod segments of tendons develop despite the absence of tendons in the autopod. Analyses of cell lineage and proliferation indicate that distinct mechanisms govern the growth of autopod and zeugopod tendon segments. To elucidate the integration of these autopod and zeugopod developmental programs, we re-examined early tendon development. At E12.5, muscles extend across the full length of a very short zeugopod and connect through short anlagen of tendon progenitors at the presumptive wrist to their respective autopod tendon segment, thereby initiating musculoskeletal integration. Zeugopod tendon segments are subsequently generated by proximal elongation of the wrist tendon anlagen, in parallel with skeletal growth, underscoring the dependence of zeugopod tendon development on muscles for tendon anchoring. Moreover, a subset of extensor tendons initially form as fused structures due to initial attachment of their respective wrist tendon anlage to multiple muscles. Subsequent individuation of these tendons depends on muscle activity. These results establish an integrated model for limb tendon development that provides a framework for future analyses of tendon and musculoskeletal phenotypes.

Certain class I HLA alleles and haplotypes implicated in susceptibility play a role in determining specific features of the psoriatic arthritis phenotype

ObjectivesPsoriatic arthritis (PsA) susceptibility is associated with several different class I alleles, suggesting separate patterns of MHC effect. This exploratory study was based on the hypothesis that heterogeneity of the...

Running on time: the role of circadian clocks in the musculoskeletal system.

The night and day cycle governs the circadian (24 hourly) rhythm of activity and rest in animals and humans. This is reflected in daily changes of the global gene expression pattern and metabolism, but also in the local physiology of various tissues. A central clock in the brain co-ordinates the rhythmic locomotion behaviour, as well as synchronizing various local oscillators, such as those found in the musculoskeletal system. It has become increasingly recognized that the internal molecular clocks in cells allow a tissue to anticipate the rhythmic changes in their local environment and the specific demands of that tissue. Consequently, the majority of the rhythmic clock controlled genes and pathways are tissue specific. The concept of the tissue-specific function of circadian clocks is further supported by the diverse musculoskeletal phenotypes in mice with deletions or mutations of various core clock components, ranging from increased bone mass, dwarfism, arthropathy, reduced muscle strength and tendon calcification. The present review summarizes the current understanding of the circadian clocks in muscle, bone, cartilage and tendon tissues, with particular focus on the evidence of circadian rhythms in tissue physiology, their entrainment mechanisms and disease links, and the tissue-specific clock target genes/pathways. Research in this area holds strong potential to advance our understanding of how circadian rhythms control the health and disease of the musculoskeletal tissues, which has major implications in diseases associated with advancing age. It could also have potential implications in sports performance and sports medicine.

Prospective signs of cleidocranial dysplasia in Cebpb deficiency.

BackgroundAlthough runt-related transcription factor 2 (RUNX2) has been considered a determinant of cleidocranial dysplasia (CCD), some CCD patients were free of RUNX2 mutations. CCAAT/enhancer-binding protein beta (Cebpb) is a key factor of Runx2 expression and our previous study has reported two CCD signs including hyperdontia and elongated coronoid process of the mandible in Cebpb deficient mice. Following that, this work aimed to conduct a case-control study of thoracic, zygomatic and masticatory muscular morphology to propose an association between musculoskeletal phenotypes and deficiency of Cebpb, using a sample of Cebpb-/-, Cebpb+/- and Cebpb+/+ adult mice. Somatic skeletons and skulls of mice were inspected with soft x-rays and micro-computed tomography (μCT), respectively. Zygomatic inclination was assessed using methods of coordinate geometry and trigonometric function on anatomic landmarks identified with μCT. Masseter and temporal muscles were collected and weighed. Expression of Cebpb was examined with a reverse transcriptase polymerase chain reaction (RT-PCR) technique.ResultsCebpb-/- mice displayed hypoplastic clavicles, a narrow thoracic cage, and a downward tilted zygomatic arch (p < 0.001). Although Cebpb+/- mice did not show the phenotypes above (p = 0.357), a larger mass percentage of temporal muscles over masseter muscles was seen in Cebpb+/- littermates (p = 0.012). The mRNA expression of Cebpb was detected in the clavicle, the zygoma, the temporal muscle and the masseter muscle, respectively.ConclusionsProspective signs of CCD were identified in mice with Cebpb deficiency. These could provide an additional aetiological factor of CCD. Succeeding investigation into interactions among Cebpb, Runx2 and musculoskeletal development is indicated.

Novel musculoskeletal phenotypes during childhood for epidemiological studies

Novel musculoskeletal phenotypes during childhood for epidemiological studies

COL6A3 Protein Deficiency in Mice Leads to Muscle and Tendon Defects Similar to Human Collagen VI Congenital Muscular Dystrophy

Collagen VI is a ubiquitously expressed extracellular microfibrillar protein. Its most common molecular form is composed of the α1(VI), α2(VI), and α3(VI) collagen α chains encoded by the COL6A1, COL6A2, and COL6A3 genes, respectively. Mutations in any of the three collagen VI genes cause congenital muscular dystrophy types Bethlem and Ullrich as well as intermediate phenotypes characterized by muscle weakness and connective tissue abnormalities. The α3(VI) collagen α chain has much larger N- and C-globular domains than the other two chains. Its most C-terminal domain can be cleaved off after assembly into microfibrils, and the cleavage product has been implicated in tumor angiogenesis and progression. Here we characterize a Col6a3 mutant mouse that expresses a very low level of a non-functional α3(VI) collagen chain. The mutant mice are deficient in extracellular collagen VI microfibrils and exhibit myopathic features, including decreased muscle mass and contractile force. Ultrastructurally abnormal collagen fibrils were observed in tendon, but not cornea, of the mutant mice, indicating a distinct tissue-specific effect of collagen VI on collagen I fibrillogenesis. Overall, the mice lacking normal α3(VI) collagen chains displayed mild musculoskeletal phenotypes similar to mice deficient in the α1(VI) collagen α chain, suggesting that the cleavage product of the α3(VI) collagen does not elicit essential functions in normal growth and development. The Col6a3 mouse mutant lacking functional α3(VI) collagen chains thus serves as an animal model for COL6A3-related muscular dystrophy.

Identification of a novel ZNF469 mutation in a large family with Ehlers–Danlos phenotype

Brittle cornea syndrome (BCS) is a genetically heterogeneous disorder characterized by extreme corneal fragility and thinning, which may lead to spontaneous or trauma-induced corneal rupture. BCS-1 and BCS-2 are caused by recessive mutations in ZNF469 and PRDM5, respectively. Both genes play a role in the regulatory pathway of corneal development and maintenance. We report a consanguineous family with five patients affected with the cardinal ocular features of BCS and significant musculoskeletal findings primarily in the form of joint hypermobility and severe kyphoscoliosis. The patients had thin velvety skin, hallux valgus, variable sensorineural hearing loss and arachnodactyly. Interestingly, one of the patients additionally had phenylketonuria and showed a milder ophthalmological and musculoskeletal phenotype than his affected siblings. The urinary pyridinoline and deoxypyridinoline concentrations and their ratios were mildly elevated indicating increased bone-collagen turnover. A novel homozygous 14bp duplication in exon 2 of ZNF469 (c.8817_8830dup) was uncovered by direct sequencing. This family highlights the phenotypic overlap between BCS and Ehlers–Danlos syndrome.

High impact activity is related to lean but not fat mass: findings from a population-based study in adolescents

Background Objective measures of physical activity calibrated against energy expenditure may have limited utility in studying relationships with musculoskeletal phenotypes. We wished to assess an alternative approach using an accelerometer calibrated according to impact loading.Methods Of the 17-year olds from the Avon Longitudinal Study of Parents and Children (ALSPAC), 732 wore Newtest accelerometers while performing day-to-day activities for a mean of 5.8 days. Outputs were categorized as light, moderate, high and very high impact, based on the thresholds identified in 22 adolescents during graded activities. In subsequent regression analyses, activity data and fat mass were normalized by log transformation.Results The number of counts relating to high impact activity was ∼2% that of light impact activity, and 33% greater in boys when compared with girls. High impact activity was more strongly related to lean mass [light: 0.033 (95% CI −0.023 to 0.089), moderate: 0.035 (95% CI −0.010 to 0.080) and high: 0.044 (95% CI 0.010 to 0.078)] (β = SD change in outcome per doubling in activity, height adjusted, boys and girls combined). In contrast, lower impact activity was more strongly related to fat mass [light: −0.069 (95% CI −0.127 to −0.011), moderate: −0.060 (95% CI −0.107 to −0.014) and high: −0.033 (95% CI −0.069 to 0.003)]. In a more fully adjusted model including other activity types and fat/lean mass, lean mass was related to only high activity (boys and girls combined), whereas fat mass was related to only moderate activity (girls only).Conclusions Using an accelerometer calibrated according to impact loading revealed that high impact activity is related to lean but not fat mass.

HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype

Rigorously ascertained cases of psoriatic arthritis in subjects presenting to a rheumatology unit were compared with cases of psoriasis in subjects presenting to a dermatology unit, where subjects with musculoskeletal features were excluded, to address 1) the extent to which the contribution of the major histocompatibility complex (MHC) to psoriatic arthritis susceptibility resembles that in psoriasis, and 2) whether MHC genes determine quantitative traits within the psoriatic arthritis phenotype. Separate discovery and validation subcohorts of patients recruited from a relatively homogeneous population were studied by sequence-based HLA typing, in which frequencies of the HLA-B and HLA-C alleles and haplotypes were compared. In patients with psoriatic arthritis, the frequency of C*06:02 was lower than that in patients with psoriasis (28.7% versus 57.5%; P = 9.9 × 10(-12) ). Three haplotypes containing B*27:05 or B*39:01 were significantly increased in frequency in patients with psoriatic arthritis, but not in those with psoriasis. The structurally related B*39:06 allele was not increased in frequency. B*27 was associated with an interval of 0.98 years between skin and musculoskeletal disease (P = 2.05 × 10(-6) ), compared with an interval of 10.14 years for C*06. Preliminary evidence suggested that B*38:01 and B*08 may be associated with psoriatic arthritis susceptibility, and that allotypes encoding P2 pockets that bind side chains opposite in charge from those encoded by the B*27 and B*39 molecules may exert a protective role. These findings suggest that the psoriasis phenotype results from two patterns of MHC effect. The first involves the classic psoriasis susceptibility gene C*06, which confers more penetrant skin disease with less prevalent and more time-dependent musculoskeletal phenotype development. The second pattern appears to be mediated by HLA-B alleles, notably B*27, and includes temporally more coincident musculoskeletal involvement that is nearly equivalent in penetrance to that of the skin disease.