No abstract

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.

No abstract

Prader-Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes within chromosome 15q11-q13. Most cases are due to paternal deletion of this region; the remaining cases result from maternal uniparental disomy (UPD) and imprinting defects. To better understand the phenotypic variability of PWS, a genotype-phenotype correlation study was performed in 91 children with PWS. Patients were diagnosed by Southern Blot Methylation assay and genetic subtypes were established using FISH and microsatellite analyses. Fifty-nine subjects with deletion (31/28 males/females; mean age 3.86 years), 30 with UPD (14/16 males/females; mean age 3.89 years) and 2 girls with a presumed imprinting defect (mean age 0.43 yrs) were identified. For correlation purposes patients were grouped as "deleted" and "non-deleted." An increased maternal age was found in the UPD group. Four of Holm's criteria were more frequently present in the deleted group: need for special feeding techniques, sleep disturbance, hypopigmentation, and speech articulation defects. Concerning cognitive assessments, only 9.52% of subjects with deletion had Full-Scale IQ (FSIQ) > or =70, while 61.53% of subjects without deletion had FSIQ > or =70. Similar results were found in behavioral measures. Sleep disorders and carbohydrate metabolism were systematically assessed. Polysomnoghaphic studies revealed a higher frequency of central events with desaturations > or =10% in the deleted group (P = 0.020). In summary, the phenotype was significantly different between both groups in certain parameters related to the CNS. These results might be related to the differences in brain gene expression of the genetic subtypes.

references presented here can also be used in other countries with similar ethnographics characteristics.