Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome

2018 ◽  
Vol 55 (12) ◽  
pp. 837-846 ◽  
Author(s):  
Stefano Paolacci ◽  
Yun Li ◽  
Emanuele Agolini ◽  
Emanuele Bellacchio ◽  
Carlos E Arboleda-Bustos ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rna Polymerase Iii ◽  
Genetic Material ◽  
Compound Heterozygous ◽  
Fatty Tissue ◽  
Functional Sites ◽  
Transcript Processing ◽  
Modelling Studies ◽  
Compound Heterozygous Variants ◽  
Biallelic Mutations

BackgroundWiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause.MethodsWe performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants.ResultsBiallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function.ConclusionBiallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.

scholarly journals Two novel biallelic mutations in PSMC3IP in a Chinese patient affected by primary ovarian insufficiency: case report and review of the literature

2021 ◽  
Author(s):  
Libin Mei ◽  
Lingling Huang ◽  
Yanru Huang ◽  
Xiaoling Wu ◽  
Huang He ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Direct Sequencing ◽  
Clinical Manifestations ◽  
Chinese Patient ◽  
Exome Capture ◽  
Compound Heterozygous ◽  
Ovarian Activity ◽  
Childbearing Age ◽  
Ovarian Insufficiency ◽  
Biallelic Mutations

Abstract Background: Premature ovarian insufficiency (POI) is a heterogeneous condition occurring when a woman experiences a loss of ovarian activity before the age of 40. It is one of the most common reproductive endocrine diseases in women of childbearing age. Here, we investigated the clinical manifestations and genetic features of a Chinese patient affected by POI.Methods: We applied next-generation whole-exome capture sequencing with Sanger direct sequencing to the proband and her clinically unaffected family members. Results: Two novel compound heterozygous mutations were identified in the PSMC3IP gene. The first is a splicing mutation (c.597+1G>T) that was inherited from her father, while the second mutation (c.268G>C p.D90H) was also discovered in her mother and younger sister. The two mutations were co-segregated with the disease phenotype in the family. Conclusions: To our knowledge, this is the first report of PSMC3IP mutations causing POI in the Chinese population. Our findings further support the key role of the PSMC3IP gene in the etiology of POI. However, additional studies are required to explore the underlying molecular mechanisms involved.

scholarly journals Fanconi–Bickel Syndrome: A Review of the Mechanisms That Lead to Dysglycaemia

2020 ◽  
Vol 21 (17) ◽  
pp. 6286
Author(s):  
Sanaa Sharari ◽  
Mohamad Abou-Alloul ◽  
Khalid Hussain ◽  
Faiyaz Ahmad Khan
Keyword(s):  
Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Poor Growth ◽  
Renal Tubular Cells ◽  
Glucose Transporter 2 ◽  
Compound Heterozygous Variants ◽  
Slc2a2 Gene

Accumulation of glycogen in the kidney and liver is the main feature of Fanconi–Bickel Syndrome (FBS), a rare disorder of carbohydrate metabolism inherited in an autosomal recessive manner due to SLC2A2 gene mutations. Missense, nonsense, frame-shift (fs), in-frame indels, splice site, and compound heterozygous variants have all been identified in SLC2A2 gene of FBS cases. Approximately 144 FBS cases with 70 different SLC2A2 gene variants have been reported so far. SLC2A2 encodes for glucose transporter 2 (GLUT2) a low affinity facilitative transporter of glucose mainly expressed in tissues playing important roles in glucose homeostasis, such as renal tubular cells, enterocytes, pancreatic β-cells, hepatocytes and discrete regions of the brain. Dysfunctional mutations and decreased GLUT2 expression leads to dysglycaemia (fasting hypoglycemia, postprandial hyperglycemia, glucose intolerance, and rarely diabetes mellitus), hepatomegaly, galactose intolerance, rickets, and poor growth. The molecular mechanisms of dysglycaemia in FBS are still not clearly understood. In this review, we discuss the physiological roles of GLUT2 and the pathophysiology of mutants, highlight all of the previously reported SLC2A2 mutations associated with dysglycaemia, and review the potential molecular mechanisms leading to dysglycaemia and diabetes mellitus in FBS patients.

scholarly journals Two novel biallelic mutations in PSMC3IP in a Chinese patient affected by primary ovarian insufficiency: case report and review of the literature

2021 ◽  
Author(s):  
Libin Mei ◽  
Lingling Huang ◽  
Yanru Huang ◽  
Xiaoling Wu ◽  
Huang He ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Direct Sequencing ◽  
Clinical Manifestations ◽  
Chinese Patient ◽  
Exome Capture ◽  
Compound Heterozygous ◽  
Ovarian Activity ◽  
Childbearing Age ◽  
Ovarian Insufficiency ◽  
Biallelic Mutations

Abstract Background: Premature ovarian insufficiency (POI) is a heterogeneous condition occurring when a woman experiences a loss of ovarian activity before the age of 40. It is one of the most common reproductive endocrine diseases in women of childbearing age. Here, we investigated the clinical manifestations and genetic features of a Chinese patient affected by POI.Methods: We applied next-generation whole-exome capture sequencing with Sanger direct sequencing to the proband and her clinically unaffected family members. Results: Two novel compound heterozygous mutations were identified in the PSMC3IP gene. The first is a splicing mutation (c.597+1G>T) that was inherited from her father, while the second mutation (c.268G>C p.D90H) was also discovered in her mother and younger sister. The two mutations were co-segregated with the disease phenotype in the family. Conclusions: To our knowledge, this is the first report of PSMC3IP mutations causing POI in the Chinese population. Our findings further support the key role of the PSMC3IP gene in the etiology of POI. However, additional studies are required to explore the underlying molecular mechanisms involved.

scholarly journals Two novel biallelic mutations in PSMC3IP in a Chinese patient affected by primary ovarian insufficiency: case report and review of the literature

2020 ◽  
Author(s):  
Libin Mei ◽  
Lingling Huang ◽  
Yanru Huang ◽  
Xiaoling Wu ◽  
Huang He ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Direct Sequencing ◽  
Clinical Manifestations ◽  
Chinese Patient ◽  
Exome Capture ◽  
Compound Heterozygous ◽  
Ovarian Activity ◽  
Childbearing Age ◽  
Ovarian Insufficiency ◽  
Biallelic Mutations

Abstract Background: Premature ovarian insufficiency (POI) is a heterogeneous condition occurring when a woman experiences a loss of ovarian activity before the age of 40. It is one of the most common reproductive endocrine diseases in women of childbearing age. Here, we investigated the clinical manifestations and genetic features of a Chinese patient affected by POI.Methods: We applied next-generation whole-exome capture sequencing with Sanger direct sequencing to the proband and her clinically unaffected family members. Results: Two novel compound heterozygous mutations were identified in the PSMC3IP gene. The first is a splicing mutation (c.597+1G>T) that was inherited from her father, while the second mutation (c.268G>C p.D90H) was also discovered in her mother and younger sister. The two mutations were co-segregated with the disease phenotype in the family. Conclusions: To our knowledge, this is the first report of PSMC3IP mutations causing POI in the Chinese population. Our findings further support the key role of the PSMC3IP gene in the etiology of POI. However, additional studies are required to explore the underlying molecular mechanisms involved.

scholarly journals Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Alicia B. Byrne ◽  
Peer Arts ◽  
Steven W. Polyak ◽  
Jinghua Feng ◽  
Andreas W. Schreiber ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Genetic Disorder ◽  
Epileptic Encephalopathy ◽  
Compound Heterozygous ◽  
Whole Exome ◽  
Sodium Dependent ◽  
Neuromotor Function ◽  
Vitamin Uptake ◽  
Compound Heterozygous Variants ◽  
Biallelic Mutations

AbstractWe describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate, and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood–brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient’s neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate, and lipoate) replacement therapy.

scholarly journals Two novel biallelic mutations in PSMC3IP in a Chinese patient affected by primary ovarian insufficiency: case report and review of the literature

2020 ◽  
Author(s):  
Libin Mei ◽  
Lingling Huang ◽  
Yanru Huang ◽  
Xiaoling Wu ◽  
Huang He ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Direct Sequencing ◽  
Clinical Manifestations ◽  
Chinese Patient ◽  
Exome Capture ◽  
Compound Heterozygous ◽  
Ovarian Activity ◽  
Childbearing Age ◽  
Ovarian Insufficiency ◽  
Biallelic Mutations

Abstract Background: Premature ovarian insufficiency (POI) is a heterogeneous condition occurring when a woman experiences a loss of ovarian activity before the age of 40. It is one of the most common reproductive endocrine diseases in women of childbearing age. Here, we investigated the clinical manifestations and genetic features of a Chinese patient affected by POI. Methods We applied next-generation whole-exome capture sequencing with Sanger direct sequencing to the proband and her clinically unaffected family members. Results Two novel compound heterozygous mutations were identified in the PSMC3IP gene. The first is a splicing mutation (c.597 + 1G > T) that was inherited from her father, while the second mutation (c.268G > C p.D90H) was also discovered in her mother and younger sister. The two mutations were co-segregated with the disease phenotype in the family. Conclusions To our knowledge, this is the first report of PSMC3IP mutations causing POI in the Chinese population. Our findings further support the key role of the PSMC3IP gene in the etiology of POI. However, additional studies are required to explore the underlying molecular mechanisms involved.

scholarly journals Two novel biallelic mutations in PSMC3IP in a Chinese patient affected by primary ovarian insufficiency: case report and review of the literature

2021 ◽  
Author(s):  
Libin Mei ◽  
Lingling Huang ◽  
Yanru Huang ◽  
Xiaoling Wu ◽  
Huang He ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Direct Sequencing ◽  
Clinical Manifestations ◽  
Chinese Patient ◽  
Exome Capture ◽  
Compound Heterozygous ◽  
Ovarian Activity ◽  
Childbearing Age ◽  
Ovarian Insufficiency ◽  
Biallelic Mutations

Abstract Background:Premature ovarian insufficiency (POI) is a heterogeneous condition occurring when a woman experiences a loss of ovarian activity before the age of 40. It is one of the most common reproductive endocrine diseases in women of childbearing age. Here, we investigated the clinical manifestations and genetic features of a Chinese patient affected by POI.Methods: We applied next-generation whole-exome capture sequencing with Sanger direct sequencing to the proband and her clinically unaffected family members. Results: Two novel compound heterozygous mutations were identified in the PSMC3IP gene. The first is a splicing mutation (c.597+1G>T) that was inherited from her father, while the second mutation (c.268G>C p.D90H) was also discovered in her mother and younger sister. The two mutations were co-segregated with the disease phenotype in the family. Conclusions: To our knowledge, this is the first report of PSMC3IP mutations causing POI in the Chinese population. Our findings further support the key role of the PSMC3IP gene in the etiology of POI. However, additional studies are required to explore the underlying molecular mechanisms involved.

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