Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.

• MeSH
• buněčné linie MeSH
• dítě MeSH
• ekzém genetika   MeSH
• genetická predispozice k nemoci genetika   MeSH
• HEK293 buňky MeSH
• imunoglobulin E krev   MeSH
• insulinu podobný růstový faktor I biosyntéza   MeSH
• kojenec MeSH
• Laronův syndrom genetika   MeSH
• lidé MeSH
• lidský růstový hormon metabolismus   MeSH
• missense mutace genetika   MeSH
• mladiství MeSH
• responzivní elementy genetika   MeSH
• transkripční faktor STAT5 genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

• MeSH
• agrekany genetika   MeSH
• antropometrie metody   MeSH
• brachydaktylie genetika   MeSH
• degenerace meziobratlové ploténky genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• heterozygot MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• mutační analýza DNA metody   MeSH
• nanismus farmakoterapie   genetika   MeSH
• osteochondritis dissecans vrozené   genetika   MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• růst genetika   MeSH
• růstový hormon terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výhřez meziobratlové ploténky genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH