Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy—Expanding the differential diagnosis for pachyonychia congenita

Saccharomyces cerevisiae strains are often host to several types of cytoplasmic double-stranded RNA (dsRNA) genomes, some of which are encapsidated by the L-A dsRNA product, an 86,000-dalton coat protein. Here we present the finding that nuclear recessive mutations in the NUC1 gene, which encodes the major nonspecific nuclease of yeast mitochondria, resulted in at least a 10-fold increase in amounts of the L-A dsRNA and its encoded coat protein. The effect of nuc1 mutations on L-A abundance was completely suppressed in strains that also hosted the killer-toxin-encoding M dsRNA. Both NUC1 and nuc1 strains containing the L-A genome exhibited an increase in coat protein abundance and a concomitant increase in L-A dsRNA when the cells were grown on a nonfermentable carbon source rather than on glucose, an effect independent of the increase in coat protein due to nuc1 mutations or to the absence of M. The increase in L-A expression in nuc1 strains was similar to that observed in strains with mutations in the nuclear gene encoding the most abundant outer mitochondrial membrane protein, porin. nuc1 mutations did not affect the level of porin in the mitochondrial outer membrane. Since the effect of mutations in nuc1 was to alter the copy number of the L-A coat protein genome rather than to change the level of the M toxin genome (as do mak and ski mutations), these mutations define a new class of nuclear genes affecting yeast dsRNA abundance.

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Pachyonychia congenita with late onset of nail dystrophy-a new clinical entity?

Clinical and Experimental Dermatology ◽

10.1111/j.1365-2230.1993.tb02257.x ◽

1993 ◽

Vol 18 (5) ◽

pp. 478-480 ◽

Cited By ~ 16

Author(s):

S. IRACI ◽

L. BTANCHI ◽

S. GATTI ◽

A.M. CARROZZO ◽

D. BETTINI ◽

...

Keyword(s):

Late Onset ◽

Clinical Entity ◽

Nail Dystrophy ◽

Pachyonychia Congenita

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Overproduction of yeast viruslike particles by strains deficient in a mitochondrial nuclease.

Molecular and Cellular Biology ◽

10.1128/mcb.9.8.3323 ◽

1989 ◽

Vol 9 (8) ◽

pp. 3323-3331 ◽

Cited By ~ 10

Author(s):

Y X Liu ◽

C L Dieckmann

Keyword(s):

Coat Protein ◽

Killer Toxin ◽

Nuclear Gene ◽

Fold Increase ◽

Mitochondrial Outer Membrane ◽

Gene Encoding ◽

Recessive Mutations ◽

A Genome ◽

Nonfermentable Carbon Source ◽

Viruslike Particles

Saccharomyces cerevisiae strains are often host to several types of cytoplasmic double-stranded RNA (dsRNA) genomes, some of which are encapsidated by the L-A dsRNA product, an 86,000-dalton coat protein. Here we present the finding that nuclear recessive mutations in the NUC1 gene, which encodes the major nonspecific nuclease of yeast mitochondria, resulted in at least a 10-fold increase in amounts of the L-A dsRNA and its encoded coat protein. The effect of nuc1 mutations on L-A abundance was completely suppressed in strains that also hosted the killer-toxin-encoding M dsRNA. Both NUC1 and nuc1 strains containing the L-A genome exhibited an increase in coat protein abundance and a concomitant increase in L-A dsRNA when the cells were grown on a nonfermentable carbon source rather than on glucose, an effect independent of the increase in coat protein due to nuc1 mutations or to the absence of M. The increase in L-A expression in nuc1 strains was similar to that observed in strains with mutations in the nuclear gene encoding the most abundant outer mitochondrial membrane protein, porin. nuc1 mutations did not affect the level of porin in the mitochondrial outer membrane. Since the effect of mutations in nuc1 was to alter the copy number of the L-A coat protein genome rather than to change the level of the M toxin genome (as do mak and ski mutations), these mutations define a new class of nuclear genes affecting yeast dsRNA abundance.

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Molecular Genetics of 3β-Hydroxy-Δ5-C27-Steroid Oxidoreductase Deficiency in 16 Patients with Loss of Bile Acid Synthesis and Liver Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-021580 ◽

2003 ◽

Vol 88 (4) ◽

pp. 1833-1841 ◽

Cited By ~ 65

Author(s):

Jeffrey B. Cheng ◽

Emmanuel Jacquemin ◽

Marie Gerhardt ◽

Hisham Nazer ◽

Danièle Cresteil ◽

...

Keyword(s):

Liver Disease ◽

Bile Acids ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Compound Heterozygous ◽

Gene Encoding ◽

Recessive Mutations ◽

Membrane Bound ◽

Heterozygous Form ◽

Progressive Liver Disease

The 3β-hydroxy-Δ5-C27-steroid oxidoreductase (C27 3β-HSD) is a membrane-bound enzyme of the endoplasmic reticulum that catalyzes an early step in the synthesis of bile acids from cholesterol. Subjects with autosomal recessive mutations in the encoding gene, HSD3B7, on chromosome 16p11.2–12 fail to synthesize bile acids and develop a form of progressive liver disease characterized by cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal tract. The gene encoding the human C27 3β-HSD enzyme was isolated previously, and a 2-bp deletion in exon 6 of HSD3B7 was identified in a well characterized subject with this disorder. Here, we report a molecular analysis of 15 additional patients from 13 kindreds with C27 3β-HSD deficiency. Twelve different mutations were identified in the HSD3B7 gene on chromosome 16p11.2–12. Ten mutations were studied in detail and shown to cause complete loss of enzyme activity and, in two cases, alterations in the size or amount of the transcribed mRNA. Mutations were inherited in homozygous form in 13 subjects from 10 families and compound heterozygous form in four subjects from three families. We conclude that a diverse spectrum of mutations in the HSD3B7 gene underlies this rare form of neonatal cholestasis.

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Generation of a Triadin KnockOut Syndrome Zebrafish Model

International Journal of Molecular Sciences ◽

10.3390/ijms22189720 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9720

Author(s):

Vanilla Martina Vecchi ◽

Marco Spreafico ◽

Alessia Brix ◽

Anna Santoni ◽

Simone Sala ◽

...

Keyword(s):

Cardiac Death ◽

Therapeutic Strategies ◽

Signal Pathways ◽

Loss Of Function ◽

Cardiac Events ◽

Malignant Phenotype ◽

Gene Encoding ◽

Zebrafish Model ◽

Recessive Mutations ◽

Cardiac Disorders

Different forms of sudden cardiac death have been described, including a recently identified form of genetic arrhythmogenic disorder, named “Triadin KnockOut Syndrome” (TKOS). TKOS is associated with recessive mutations in the TRDN gene, encoding for TRIADIN, but the pathogenic mechanism underlying the malignant phenotype has yet to be completely defined. Moreover, patients with TKOS are often refractory to conventional treatment, substantiating the need to identify new therapeutic strategies in order to prevent or treat cardiac events. The zebrafish (Danio rerio) heart is highly comparable to the human heart in terms of functions, signal pathways and ion channels, representing a good model to study cardiac disorders. In this work, we generated the first zebrafish model for trdn loss-of-function, by means of trdn morpholino injections, and characterized its phenotype. Although we did not observe any gross cardiac morphological defect between trdn loss-of-function embryos and controls, we found altered cardiac rhythm that was recovered by the administration of arrhythmic drugs. Our model will provide a suitable platform to study the effect of TRDN mutations and to perform drug screening to identify new pharmacological strategies for patients carrying TRDN mutations.

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Goldberg-Shprintzen syndrome protein KIF1BP is a CITK interactor implicated in cytokinesis.

Journal of Cell Science ◽

10.1242/jcs.250902 ◽

2021 ◽

Author(s):

Gianmarco Pallavicini ◽

Marta Gai ◽

Giorgia Iegiani ◽

Gaia Elena Berto ◽

Annie Adrait ◽

...

Keyword(s):

Intellectual Disability ◽

Hirschsprung Disease ◽

Facial Features ◽

Gene Encoding ◽

Physiological Conditions ◽

Recessive Mutations ◽

Microtubule Stability ◽

Chromosome Passenger Complex ◽

Syndrome Protein ◽

Kinesin Family

Goldberg-Shprintzen disease (GOSHS) is a rare microcephaly syndrome accompanied by intellectual disability, dysmorphic facial features, peripheral neuropathy and Hirschsprung disease. It is associated with recessive mutations in the gene encoding kinesin family member 1-binding protein (KIF1BP). The encoded protein regulates axon microtubules dynamics, kinesin attachment and mitochondrial biogenesis, but it is not clear how its loss could lead to microcephaly. We identified KIF1BP in the interactome of Citron Kinase (CITK), a protein produced by primary hereditary microcephaly 17 (MCPH17) gene. KIF1BP and CITK interact under physiological conditions in mitotic cells. Similar to CITK, KIF1BP is enriched at the midbody ring and is required for cytokinesis. The association between KIF1BP and CITK can be influenced by CITK activity and the two proteins may antagonize each other for their midbody localization. KIF1BP knockdown decreases microtubule stability, increases KIF23 midbody levels and impairs midbody localization of KIF14, as well as of Chromosome Passenger Complex. These data indicate that KIF1BP is a CITK interactor involved in midbody maturation and abscission and suggest that cytokinesis failure may contribute to the microcephaly phenotype observed in GOSHS.

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Genetically determined susceptibility to mycobacterial infection

Journal of Clinical Pathology ◽

10.1136/jcp.2007.051201 ◽

2008 ◽

Vol 61 (9) ◽

pp. 1006-1012 ◽

Cited By ~ 29

Author(s):

S Y Patel ◽

R Doffinger ◽

G Barcenas-Morales ◽

D S Kumararatne

Keyword(s):

Mycobacterial Infection ◽

Surface Expression ◽

Interferon Γ ◽

Cell Surface Expression ◽

Interleukin 12 ◽

Genetic Defects ◽

Cell Mediated Immunity ◽

Gene Encoding ◽

Mycobacterial Infections ◽

Recessive Mutations

Individuals with impaired cell mediated immunity exhibit increased susceptibility to infections caused by poorly pathogenic mycobacteria (non-tuberculous mycobacteria and BCG), as well as salmonella species. However, these infections may also occur in a disseminated, fatal form, sometimes with a familial distribution, in the absence of any recognised primary or secondary immunodeficiency. Genetic analysis of affected families has defined mutations in seven different genes participating in the interleukin 12 (IL12) dependent, high output interferon γ (IFNγ) pathway. The first category of defect is mutations in the IFNγR1 or R2 genes, resulting in defective expression or function of the IFNγ receptor. The second category of mutations abrogates the cell surface expression IL12Rβ1gene, resulting in the inability to respond to IL12. The third category of defect is the inability to produce IL12, due to deletion within the gene coding for the inducible chain of IL12 (IL12-p40). Patients with X-linked recessive mutations of the gene encoding the NFκB essential modulator may also develop mycobacterial infections, although they usually have a more complex phenotype and are susceptible to a broad spectrum of pathogens. Mutations of the gene encoding the signal transducing molecule STAT1, which impairs the ability to respond to IFNγ, and mutations of the gene encoding TYK2 (which is associated with a failure to respond to IL12), are both rare genetic defects predisposing to mycobacterial infections. This review summarises the clinical spectrum seen in this group of patients and indicates a strategy for the identification of putative genetic defects in the type-1 cytokine pathway.

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Microcephaly-Capillary Malformation Syndrome

Journal of Pediatric Neurology ◽

10.1055/s-0038-1667134 ◽

2018 ◽

Vol 16 (05) ◽

pp. 319-327

Author(s):

Agata Polizzi ◽

Maria Garozzo ◽

Concetta Pirrone ◽

Antonio Zanghì ◽

Stefania Salafia ◽

...

Keyword(s):

Autosomal Recessive ◽

Intractable Epilepsy ◽

Research Groups ◽

Optic Nerve Atrophy ◽

Older Patient ◽

Nail Dystrophy ◽

Life Data ◽

Recessive Mutations ◽

Capillary Malformation ◽

High Penetrance

AbstractMicrocephaly-capillary malformation is a relatively new syndrome, which has been reported since 2011 by three different research groups. It is an ultra-rare syndrome characterized by the co-occurrence of microcephaly and multiple capillary malformations in the skin, distal limb anomalies (ranging from nail dystrophy to total absence of one or more phalanxes and mostly localized in the foot), facial dysmorphisms, brain structural anomalies (reduced gyration, widened axial spaces, thin cortex, optic nerve atrophy), early-onset severe intractable epilepsy, and profound mental delay. Autosomal recessive mutations in STAMBP gene (2p13.1) have been reported as the only cause of the disorder, with a high penetrance. Currently, no definitive cure is available for the disorder, and treatment is mainly based on multiple antiepileptic drugs for the treatment of seizures, especially in the first years of life. Data on life-long concerns have not been reported, the older patient described so far being an 8-year-old boy.

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Histopathological and Molecular Features of a Conjunctival Caruncular Deep Penetrating Nevus

Ocular Oncology and Pathology ◽

10.1159/000504966 ◽

2020 ◽

Vol 6 (4) ◽

pp. 293-296

Author(s):

Jolique A. van Ipenburg ◽

Jeffrey Damman ◽

Dion Paridaens ◽

Robert M. Verdijk

Keyword(s):

Differential Diagnosis ◽

Histological Examination ◽

Molecular Level ◽

Melanocytic Nevus ◽

Braf V600e Mutation ◽

Braf V600e ◽

Melanocytic Lesion ◽

Gene Encoding ◽

Spitz Nevus ◽

Molecular Features

We describe the first presentation of a deep penetrating nevus (DPN) on the lacrimal caruncle. This lesion was seen in an 18-year-old woman presenting with hemorrhage of a long-standing pigmented mass on the caruncle. Histology showed a combined melanocytic neoplasm that consisted of two different melanocytic components. The differential diagnosis, based on histological examination, was a conventional melanocytic nevus, a Spitz nevus, or a combined melanocytic nevus. On the molecular level, one of the components revealed a mutation in the CTNNB1 gene encoding the β-catenin protein, while both components harbored a BRAF V600E mutation, without molecular features of a malignant melanocytic lesion. This presentation of a DPN of the lacrimal caruncle emphasizes the similarities of the caruncle with the skin.

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