Search

Members of the AAA+ superfamily of ATPases are involved in the unfolding of proteins and disassembly of protein complexes and aggregates. ATAD1 encoding the ATPase family, AAA+ domain containing 1-protein Thorase plays an important role in the function and integrity of mitochondria and peroxisomes. Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2. Using whole-exome sequencing, we identified a homozygous frameshift mutation in the last exon of ATAD1 [c.1070_1071delAT; p.(His357Argfs*15)] in three siblings who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes. Atad1-/- neurons expressing Thorase mutantHis357Argfs*15 display reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane. Taken together, our molecular and functional analyses identify an activating ATAD1 mutation as a new cause of severe encephalopathy and congenital stiffness. [ABSTRACT FROM AUTHOR]

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10 -knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease’s effect in humans. Fibroblasts derived from affected individuals and Cdk10 -knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10 -knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development. [ABSTRACT FROM AUTHOR]

Abstract: We describe a multiple malformation syndrome comprising coronal craniosynostosis, unilateral radial ray hypoplasia and diaphragmatic hernia in a 33w female fetus born to a 46 y-old male with an alleged personal and family history of Crouzon syndrome. By identifying an already described c.445C>T TWIST missense mutation, we were able to reassign the diagnosis of the family condition to Saethre-Chötzen syndrome. The present report illustrates clinical variability of a dominantly inherited TWIST mutation and provides a third example of Baller-Gerold/Saethre-Chötzen overlapping phenotype. We also add diaphragmatic hernia in the spectrum of TWIST-related malformations, although we couldn''t prove the co-occurrence is not coincidental. [Copyright &y& Elsevier]

Abstract: Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund–Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia, gingivitis, nail dystrophy, palmoplantar keratoderma and pachyonychia of the great toenails. Previously undetected and silent neutropenia was evidenced after C16orf57 molecular analysis. Neutropenia was absent in the C16orf57-negative patients. This report confirms that neutrophil count should be performed in all patients with poikiloderma to target the C16orf57 gene sequencing analysis, prior to RECQL4 analysis. [Copyright &y& Elsevier]

The Dual-specify tyrosine phosphorylation-regulated kinase 1A ( DYRK1A ) gene has been extensively studied for its role in the pathophysiology of intellectual disability (ID) in Down syndrome. The rise of next generation sequencing (NGS) and array-CGH (aCGH) in diagnostic settings for the evaluation of patients with ID allowed the identification of 17 patients carrying heterozygous genetic aberrations involving DYRK1A to date. The rate of DYRK1A mutations in this population reaches >1% in published NGS studies. The current report aims at further defining the phenotype of this encephalopathy with the detailed report of two unrelated patients. Both patients were boys with developmental delay, febrile seizures, facial dysmorphism and brain atrophy on MRI. Patient #1 had autistic behaviors and micropenis and Patient #2 had stereotypies and microcephaly. NGS analyses identified heterozygous de novo variants in DYRK1A : the c.613C >T (p.Arg205*) nonsense mutation in Patient #1 and the c.932C >T (p.Ser311Phe) missense mutation in Patient #2. Together with previously reported cases, patients with DYRK1A mutations share many clinical features and may have a recognizable phenotype that includes, by decreasing order of frequency: developmental delay or ID with behaviors suggesting autism spectrum disorder, microcephaly, epileptic seizures, facial dysmorphism including ear anomalies (large ears, hypoplastic lobes), thin lips, short philtrum and frontal bossing. Delineation of the phenotype/genotype correlation is not feasible at the moment and will be a challenge for the coming years. [ABSTRACT FROM AUTHOR]

A narrow thorax with shortening of long bones is usually pointing to dysfunction of the primary cilia corresponding clinically to ciliopathies with major skeletal involvement. Mutations in at least 23 genes are likely to correspond to this clinical presentation: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586. In addition to these, KIAA0753 variants were recently described in seven patients with Jeune asphyxiating thoracic dystrophy (ATD) (two first cousins, one unrelated patient and one fetus), Joubert syndrome (two siblings) and orofaciodigital syndrome type 6 (one patient). We present the clinical characteristics of a eighth such patient. This 4 year-old boy with narrow thorax, short limbs, severe respiratory and feeding difficulties from birth on had a history of hypotonia and developmental delay. On skeletal survey, short tubular bones (height - 5,5 SD) and a trident appearance of the pelvis were seen. Brain MRI showed cervical canal stenosis. Renal function was normal and moderate hepatomegaly was noted. A homozygous c.943C > T mutation in KIAA0753 was identified on whole exome sequencing, resulting in Gln315Ter premature termination of the corresponding protein. This case provides confirmation of an additional molecular basis for skeletal dysplasia and illustrates how ciliopathies due to mutations in a single gene may present as apparently distinct syndromes. [ABSTRACT FROM AUTHOR]