A novel deletion mutation in the TUSC3 gene in a consanguineous Pakistani family with autosomal recessive nonsyndromic intellectual disability

<p>Abstract</p> <p>Background</p> <p>Intellectual disability (ID) is a serious disorder of the central nervous system with a prevalence of 1-3% in a general population. In the past decades, the research focus has been predominantly on X-linked ID (68 loci and 19 genes for non syndromic X linked ID) while for autosomal recessive nonsyndromic ID (NSID) only 30 loci and 6 genes have been reported to date.</p> <p>Methods</p> <p>Genome-wide homozygosity mapping with 500 K Nsp1 array (Affymetrix), CNV analysis, PCR based breakpoint mapping and DNA sequencing was performed to explore the genetic basis of autosomal recessive nonsyndromic ID in a large Pakistani family.</p> <p>Results</p> <p>Data analysis showed linkage at 8p23 locus with common homozygous region between SNPs rs6989820 and rs2237834, spanning a region of 12.494 Mb. The subsequent CNV analysis of the data revealed a homozygous deletion of 170.673 Kb which encompassed the <it>TUSC3 </it>gene.</p> <p>Conclusion</p> <p>We report a novel deletion mutation in <it>TUSC3 </it>gene which is the second gene after <it>TRAPPC9 </it>in which mutation has been identified in more than one family with autosomal recessive NSID. The study will aid in exploring the molecular pathway of cognition.</p

Substrate interaction defects in histidylâ tRNA synthetase linked to dominant axonal peripheral neuropathy

Histidylâ tRNA synthetase (HARS) ligates histidine to cognate tRNA molecules, which is required for protein translation. Mutations in HARS cause the dominant axonal peripheral neuropathy Charcotâ Marieâ Tooth disease type 2W (CMT2W); however, the precise molecular mechanism remains undefined. Here, we investigated three HARS missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The three mutations localize to the HARS catalytic domain and failed to complement deletion of the yeast ortholog (HTS1). Enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultracentrifugation (AUC) were employed to assess the effect of these substitutions on primary aminoacylation function and overall dimeric structure. Notably, the p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly HARS substitutions all led to reduced aminoacylation, providing a direct connection between CMT2Wâ linked HARS mutations and loss of canonical ARS function. While DSF assays revealed that only one of the variants (p.Val155Gly) was less thermally stable relative to wildâ type, all three HARS mutants formed stable dimers, as measured by AUC. Our work represents the first biochemical analysis of CMTâ associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology.Diseaseâ causing variants in multiple aminoacylâ tRNA synthetase genes have been linked to the dominant inherited peripheral neuropathy Charcot Marie Tooth (CMT) disease. Here, we employed yeast complementation, enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultra centrifugation (AUC) to investigate three histidylâ tRNA synthetase (HARS) missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The mutant substitutions all led to reduced catalytic activity and poorer histidine and ATP binding, illustrating how loss of primary aminoacylation function can contribute to disease pathology.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142441/1/humu23380_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142441/2/humu23380.pd

L1CAM mutation in association with X-linked hydrocephalus and Hirschsprung’s disease

X-linked hydrocephalus (XLH) is characterized by increased intracranial ventricle size and head circumference secondary to aqueduct of Sylvius congenital stenosis. Exceedingly rare is the concurrence of XLH and Hirschsprung’s disease (HSCR) with a theoretical incidence of 1 in 125–250 million cases. Herein, we are describing a case of a patient with concurrent XLH and HSCR. The patient was delivered via cesarean section at 37 weeks gestation and underwent uneventful ventriculoperitoneal shunt placement. As a part of a workup for constipation, we performed a rectal biopsy, which was consistent with HSCR. Genetics testing showed hemizygous for R558X hemizygous mutation in the L1CAM gene. A C → T nucleotide substitution in exon 13 resulted in replacement of an arginine codon with a stop codon, a nonsense mutation. Although it is widely accepted that HSCR represents the failure of early embryonic neural crest cells to migrate properly, the exact mechanism is not known. The association of HSCR with XLH in the presence of L1CAM mutations remains quite interesting because cell adhesion molecules are involved in the proper migration of neural components throughout the body. Additional studies are necessary to fully elucidate the relationship between XLH and HSCR in the presence of L1CAM mutations

Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6+/−;Grhl3+/−) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS

HAI-2 stabilizes, inhibits, and regulates SEA-cleavage-dependent secretory transport of matriptase

It has recently been shown that HAI-2 is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In the present study we describe three mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F, and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the ER. We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation, and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L, C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization, and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway

Novel association of severe neonatal encephalopathy and Hirschsprung disease in a male with a duplication at the Xq28 region

<p>Abstract</p> <p>Background</p> <p>Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of parasympathetic intrinsic ganglion cells in the submucosal and myenteric plexuses along a variable portion of the intestinal tract. In approximately 18% of the cases HSCR also presents with multiple congenital anomalies including recognized syndromes.</p> <p>Methods</p> <p>A combination of MLPA and microarray data analysis have been undertaken to refine a duplication at the Xq28 region.</p> <p>Results</p> <p>In this study we present a new clinical association of severe neonatal encephalopathy (Lubs syndrome) and HSCR, in a male patient carrying a duplication at the Xq28 region which encompasses the <it>MECP2 </it>and <it>L1CAM </it>genes.</p> <p>Conclusions</p> <p>While the encephalopathy has been traditionally attributed to the <it>MECP2 </it>gene duplication in patients with Lubs syndrome, here we propose that the enteric phenotype in our patient might be due to the dosage variation of the L1CAM protein, together with additional molecular events not identified yet. This would be in agreement with the hypothesis previously forwarded that mutations in <it>L1CAM </it>may be involved in HSCR development in association with a predisposing genetic background.</p

Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis-intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new” syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome”

Oxidative stress and adrenocortical insufficiency

This work has been supported by the Wellcome Trust (Clinical Research Training Fellowship grant number WT095984AIA to R P) and the Medical Research Council UK (project grant number MR/K020455/1 to L A M

Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

Peer reviewe