<i>PAPSS2</i>mutations cause autosomal recessive brachyolmia

Miyake, Noriko; Elçioğlu, Nursel; Iida, Aritoshi; İşgüven, Pınar; Dai, Jin; Murakami, Nobuyuki; Takamura, Kei; Cho, Tae Joon; Kim, Ok Hwa; Hasegawa, Tomonobu; Nagai, Toshiro; Ohashi, Hirofumi; Nishimura, Gen; Matsumoto, Naomichi; Ikegawa, Shiro

doi:10.1136/jmedgenet-2012-101039

Cited by 48 publications

(61 citation statements)

References 18 publications

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“…This disorder is characterized by short limbs and pulmonary hypoplasia due to abnormal skeletal development [69–71]. Loss-of-function mutations in PAPSS2 are associated with a type of dwarfism called brachyolmia type 4, a non-lethal genetic disorder that affects the spine [72]. Some, PAPSS2 mutations can lead to brachyolmia or more severe skeletal disorders such as spondyloepimetaphyseal dysplasia Pakisani type, characterized by a number of abnormalities in the skeleton and the cartilage between long bones resulting in short stature and bowed legs.…”

Section: Sulfonation In the Context Of Diseases And Cancermentioning

confidence: 99%

Sulfonation, an underexploited area: from skeletal development to infectious diseases and cancer

2016

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Sulfonation is one of the most abundant cellular reactions modifying a wide range of xenobiotics as well as endogenous molecules which regulate important biological processes including blood clotting, formation of connective tissues, and functionality of secreted proteins, hormones, and signaling molecules. Sulfonation is ubiquitous in all tissues and widespread in nature (plants, animals, and microorganisms). Although sulfoconjugates were discovered over a century ago when, in 1875, Baumann isolated phenyl sulfate in the urine of a patient given phenol as an antiseptic, the significance of sulfonation and its roles in human diseases have been underappreciated until recent years. Here, we provide a current overview of the significance of sulfonation reactions in a variety of biological functions and medical conditions (with emphasis on cancer). We also discuss research areas that warrant further attention if we are to fully understand how deficiencies in sulfonation could impact human health which, in turn, could help define treatments to effect improvements in health.

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Section: Sulfonation In the Context Of Diseases And Cancermentioning

confidence: 99%

Sulfonation, an underexploited area: from skeletal development to infectious diseases and cancer

2016

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“…Autosomal recessive brachyolmia, which is a heterogeneous group of skeletal dysplasias and primarily affects the spine, is also caused by PAPSS2 mutations [46, 47]. Brachyolmia is characterized by a short stature due to a short trunk, irregular endoplates, a narrow intervertebral disc, calcification of cartilage in the ribs, a short femoral neck and metacarpals, and normal intelligence [46–48].…”

Section: Human Disorders Affecting the Skeleton And Skin Due To Thmentioning

confidence: 99%

“…Brachyolmia is characterized by a short stature due to a short trunk, irregular endoplates, a narrow intervertebral disc, calcification of cartilage in the ribs, a short femoral neck and metacarpals, and normal intelligence [46–48]. However, the excess amount of androgens cannot be detected in these patients.…”

Section: Human Disorders Affecting the Skeleton And Skin Due To Thmentioning

confidence: 99%

Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

Mizumoto

Yamada

Sugahara

2014

BioMed Research International

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Glycosaminoglycans (GAGs) are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases and sulfotransferases. The structural diversity of GAG polysaccharides, including their sulfation patterns and sequential arrangements, is essential for a wide range of biological activities such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Studies using knockout mice of enzymes responsible for the biosynthesis of the GAG side chains of proteoglycans have revealed their physiological functions. Furthermore, mutations in the human genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs cause a number of genetic disorders including chondrodysplasia, spondyloepiphyseal dysplasia, and Ehlers-Danlos syndromes. This review focused on the increasing number of glycobiological studies on knockout mice and genetic diseases caused by disturbances in the biosynthetic enzymes for GAGs.

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“…Further, our cisexpression analysis revealed an association between the index SNP and PAPSS2 gene expression. Although MINPP1 and PTEN are other logical candidates in this region, we did not detect significant (21,22) and spondyloepimetaphyseal dysplasia (23). It is likely that this premature onset of joint degeneration is due to impaired proteoglycan sulfation.…”

Section: Discussionmentioning

confidence: 87%

Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence forPAPSS2as a Longevity Gene

Yerges‐Armstrong

Chai

O’Connell

et al. 2016

GERONA

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Although there is compelling evidence for a genetic contribution to longevity, identification of specific genes that robustly associate with longevity has been a challenge. In order to identify longevity-enhancing genes, we measured differential gene expression between offspring of long-lived Amish (older than 90 years; cases, n = 128) and spouses of these offspring (controls, n = 121) and correlated differentially expressed transcripts with locations of longevity-associated variants detected in a prior genome-wide association study (GWAS) of survival to age 90. Expression of one of these transcripts, 3′-phosphoadenosine 5′-phosphosulfate synthase 2 (PAPSS2), was significantly higher in offspring versus controls (4 × 10 −4 ) and this association was replicated using quantitative real-time polymerase chain reaction. PAPSS2, a sulfation enzyme located on chromosome 10, is ~80 kb upstream of the PAPSS2 transcription start site. We found evidence of cis-expression for the originally reported GWAS SNP and PAPSS2. Monogenic conditions linked to PAPSS2 include andrenocortical androgen excess resulting in premature pubarche and skeletal dysplasias, both of which have premature aging features. In summary, these findings provide novel evidence for PAPSS2 as a longevity locus and illustrate the value of harnessing multiple "-omic" approaches to identify longevity candidates. Keywords: Longevity genetics-Gene expression-PAPSS2Life span is the result of a complicated interplay between genetic and environmental factors. Although much of the genetic research on aging has focused on predisposition of age-related diseases such as cardiovascular and Alzheimer's disease, compelling evidence from animal models and human studies supports the existence of genetic factors that enhance life span itself by influencing cellular aging (1-3).Studies of twins reared together and twins reared apart suggest that genetic factors explained ~30% of the variance in longevity (4,5), and heritability of life span in the Old Order Amish was previously estimated as ~25% (6). A stronger genetic influence on longevity has been reported for more extreme life-span phenotypes (eg, premature death or exceptional survival) than for life span in general (7,8). A study by Perls and colleagues demonstrated that the siblings of centenarians are 8-17 times more likely to survive to age 100 compared with other individuals from their birth cohorts (9). Ashkenazi parents of centenarians were approximately seven times more likely to live to age 90 (10), and the Leiden Longevity Study found that mortality rates in first-degree relatives of long-lived individuals were 30% lower compared with the general population (11). These studies support the concept that longevity is a familial trait likely to be inherited and demonstrate the potential utility of using family studies in identifying longevity assurance genes.

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PAPSS2mutations cause autosomal recessive brachyolmia

Abstract: We identified PAPSS2 as the disease gene for an AR brachyolmia. PAPSS2 mutations have produced a skeletal dysplasia family, with a gradation of phenotypes ranging from brachyolmia to spondylo-epi-metaphyseal dysplasia.

Cited by 48 publications

References 18 publications

Sulfonation, an underexploited area: from skeletal development to infectious diseases and cancer

Sulfonation, an underexploited area: from skeletal development to infectious diseases and cancer

Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence forPAPSS2as a Longevity Gene

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