Human Mutation

doi: 10.1002/humu.22020pmid: 22213154

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal‐dominant disorder characterized by ocular and renal malformations. Mutations in the paired‐box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus‐specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. Hum Mutat 33:457–466, 2012. © 2011 Wiley Periodicals, Inc.

Chronic granulomatous disease (CGD) is mainly caused by mutations in X‐linked CYBB that encodes gp91. We have identified two novel mutations in CYBB resulting in the rare X91+‐CGD variant, c.1500T>G (p.Asp500Glu) in two male siblings and c.1463C>A (p.Ala488Asp) in an unrelated male. Zymosan and/or PMA (Phorbol 12‐myristate 13‐acetate)‐induced recruitment of p47phox and p67phox to the membrane fraction was normal for both mutants. Cell‐free assays using recombinant wild‐type and the mutant proteins revealed that these mutants were not activated by NADPH (nicotinamide adenine dinucleotide phosphate). Interestingly, the Ala488Asp mutant was activated by NADPH in the presence of glutathione. These data suggest that the mutations prevented NADPH from binding to gp91phox and the requirement of a negative charge at residue 500 in gp91phox for NADPH oxidase assembly, in contrast to a previously described Asp500Gly change. These mutations and the effect of glutathione provide a unique insight into disease pathogenesis and potential therapy in variant X91+‐CGD. Hum Mutat 33:471–475, 2012. © 2011 Wiley Periodicals, Inc.

doi: 10.1002/humu.22007pmid: 22161988

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Previously, we demonstrated that pathogenic amino acid substitutions in the N‐terminal domain of TSC1 (amino acids 50–224) are destabilizing. Here we investigate an additional 21 unclassified TSC1 variants. Our functional assessment identified four substitutions (p.L61R, p.G132D, p.F158S, and p.R204P) between amino acids 50 and 224 that reduced TSC1 stability and prevented the TSC1‐TSC2‐dependent inhibition of TORC1. In four cases (20%), our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our new data confirm our previous finding that the N‐terminal region of TSC1 is essential for TSC1 function. Hum Mutat 33:476–479, 2012. © 2011 Wiley Periodicals, Inc.

doi: 10.1002/humu.22014pmid: 22190470

Inhibitory costimulatory molecule CD274 expresses in various cancers and contributes to cancer immune evasion by inhibiting T cell activation and proliferation, yet the regulatory mechanisms for CD274 overexpression in cancers are poorly understood. In this study, we discovered a novel mechanism of CD274 expression regulated by miR‐570. A guanine‐to‐cytosine mutation at the 3′‐UTR of CD274 mRNA led to CD274 overexpression by disrupting the miR‐570 binding. The mutations were widely observed in cancers by sequencing of 276 gastrointestinal cancers (esophageal, gastric, colorectal, hepatocellular, and pancreatic cancers). This mutation was significantly associated with CD274 overexpression in gastric cancer (P = 1.44×10−10) and with the pathological features including differentiation grade, depth of tumor invasion, lymph node metastasis, and tumor‐node‐metastases (TNM) stage. These findings suggest a novel regulatory mechanism for CD274 overexpression in gastric cancer mediated by miR‐570 and a somatic mutation in CD274 3′‐UTR, and provide a new insight to gastric carcinogenesis. Hum Mutat 33:480–484, 2012. © 2011 Wiley Periodicals, Inc.

doi: 10.1002/humu.22019pmid: 22213132

Congenital disorders of glycosylation (CDG) comprise a clinically and biochemically heterogeneous group of monogenetic‐inherited, multisystemic diseases that affect the biosynthesis of N‐ and/or O‐glycans linked to glycoconjugates. Recently, we identified the first patient with a defect in the cytosolic‐orientated GDP‐mannose:Man3‐4GlcNAc2‐PP‐dolichol alpha‐1,2‐mannosyltransferase (ALG11), who presented an accumulation of shortened dolichol‐linked oligosaccharides leading to CDG‐Ip (ALG11‐CDG). Here we describe an improved metabolic labeling method that allowed the identification of three new CDG‐Ip cases that were missed so far in routine diagnostics. Although all CDG‐Ip patients carry different mutations in the ALG11 gene, they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the first year of life. Hum Mutat 33:485–487, 2012. © 2011 Wiley Periodicals, Inc.