Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

Achromatopsia is an autosomal recessive disorder characterized by cone photoreceptor dysfunction. We recently identified activating transcription factor 6 (ATF6) as a genetic cause of achromatopsia. ATF6 is a key regulator of the unfolded protein response. In response to endoplasmic reticulum (ER) stress, ATF6 migrates from the ER to Golgi to undergo regulated intramembrane proteolysis to release a cytosolic domain containing a basic leucine zipper (bZIP) transcriptional activator. The cleaved ATF6 fragment migrates to the nucleus to transcriptionally up-regulate protein-folding enzymes and chaperones. ATF6 mutations in patients with achromatopsia include missense, nonsense, splice site, and single-nucleotide deletion or duplication changes found across the entire gene. Here, we comprehensively tested the function of achromatopsia-associated ATF6 mutations and found that they group into three distinct molecular pathomechanisms: class 1 ATF6 mutants show impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity; class 2 ATF6 mutants bear the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress; and class 3 ATF6 mutants have complete loss of transcriptional activity because of absent or defective bZIP domains. Primary fibroblasts from patients with class 1 or class 3 ATF6 mutations show increased cell death in response to ER stress. Our findings reveal that human ATF6 mutations interrupt distinct sequential steps of the ATF6 activation mechanism. We suggest that increased susceptibility to ER stress-induced damage during retinal development underlies the pathology of achromatopsia in patients with ATF6 mutations.cone photoreceptor | achromatopsia | endoplasmic reticulum stress | ATF6 | unfolded protein response A chromatopsia is a heritable blinding disease caused by cone photoreceptor dysfunction that spares the rod system. Using next-generation whole-exome sequencing, we recently discovered autosomal recessive mutations in the activating transcription factor 6 (ATF6) gene in patients with achromatopsia (1). ATF6 mutations span the entire coding region and include missense, nonsense, splice site, and single-nucleotide deletion and duplication changes (1-3). We previously showed that a missense mutation that introduced an arginine-to-cysteine substitution at amino acid residue 324 of the ATF6 protein compromised ATF6 activity in patient fibroblasts obtained from an achromatopsia family (1). However, the functional consequences of the other ATF6 mutations found in patients with achromatopsia remain unknown.In humans, ATF6 is a 670-amino acid glycosylated transmembrane protein found in the endoplasmic reticulum (ER) (4). In response to protein misfolding in the ER or other forms of ER stress, ATF6 migrates from the ER to the Golgi apparatus, where the site 1 protease (S1P) and site 2 protease (S2P) cleave ATF6 in the transmembrane domain to liberate the cyt...

BackgroundTo explore the current models of practice in centres delivering specialist care for children with disorders of sex development (DSD), an international survey of 124 clinicians, identified through DSDnet and the I-DSD Registry, was performed in the last quarter of 2014.ResultsA total of 78 (63 %) clinicians, in 75 centres, from 38 countries responded to the survey. A formal national network for managing DSD was reported to exist in 12 (32 %) countries. The paediatric specialists routinely involved in the initial evaluation of a newborn included: endocrinologist (99 %), surgeon/urologist (95 %), radiologist (93 %), neonatologist (91 %), clinical geneticist (81 %) and clinical psychologist (69 %). A team consisting of paediatric specialists in endocrinology, surgery/urology, clinical psychology, and nursing was only possible in 31 (41 %) centres. Of the 75 centres, 26 (35 %) kept only a local DSD registry and 40 (53 %) shared their data in a multicentre DSD registry. Attendance in local, national and international DSD-related educational programs was reported by 69, 78 and 84 % clinicians, respectively. Participation in audits/quality improvement exercises in DSD care was reported by 14 (19 %) centres. In addition to complex biochemistry and molecular genetic investigations, 40 clinicians (51 %) also had access to next generation sequencing. A genetic test was reported to be more preferable than biochemical tests for diagnosing 5-alpha reductase deficiency and 17-beta hydroxysteroid dehydrogenase 3 deficiency by 50 and 55 % clinicians, respectively.ConclusionDSD centres report a high level of interaction at an international level, have access to specialist staff and are increasingly relying on molecular genetics for routine diagnostics. The quality of care provided by these centres locally requires further exploration.

Aniridia is a rare, panocular disorder characterized by a variable degree of hypoplasia or the absence of iris tissue associated with additional ocular abnormalities. It is inherited in an autosomal dominant manner, with high penetrance and variable expression even within the same family. In most cases the disease is caused by haploinsufficiency truncating mutations in the PAX6 gene; however, in up to 30% of aniridia patients, disease results from chromosomal rearrangements at the 11p13 region. The aim of this review is to present the clinical and genetic aspects of the disease. Furthermore, we present a molecular diagnostic strategy in the aniridia patients. Recent improvement in the genetic diagnostic approach will precisely diagnosis aniridia patients, which is essential especially for children with aniridia in order to determine the risk of developing a Wilms tumor or neurodevelopmental disorder. Finally, based on the previous studies we describe the current knowledge and latest research findings in the topic of pathogenesis of aniridia and possible future treatment.

Aim: A secular trend in body height and weight is well documented. The first observations concerning this phenomenon in Poland were made at the end of the 19th century. The aim of this study was to assess changes in body height and weight during the 20th century, with special emphasis on the last decade. Methods: The results of body height and weight measurements obtained in eight subsequent surveys (1880–1886, 1922–1927, 1946–1950, 1960–1961, 1970–1971, 1980–1981, 1990–1991 and 1999–2000) were included in the analysis. Mean values were compared and differences between the surveys were analysed. Results: In general, in the 20th century, children grew taller and heavier and reached final body height and weight more rapidly. The biggest differences in body height and weight in the 20th century, observed at growth spurt, were about 17 cm and 11kg, respectively, for boys, and 13 cm and 13 kg for girls. The magnitude of secular changes in body height and weight in the 20th century was not stable. There were periods of increased and decreased intensity of acceleration of physical development (the 1950s and 1970s, and the 1960s and 1980s, respectively), as well as a period of deceleration (the 1940s). In the last decade, the tendency has been towards deceleration in most age groups studied. Conclusion: The acceleration of physical development in children in Poznan has now ceased.