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Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.

Abstract：

:EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Oud MM,Tuijnenburg P,Hempel M,van Vlies N,Ren Z,Ferdinandusse S,Jansen MH,Santer R,Johannsen J,Bacchelli C,Alders M,Li R,Davies R,Dupuis L,Cale CM,Wanders RJA,Pals ST,Ocaka L,James C,Müller I,Lehmberg K,Strom T

doi

10.1016/j.ajhg.2017.01.013

subject

Has Abstract

pub_date

2017-02-02 00:00:00

pages

281-296

issue

2

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(17)30013-7

journal_volume

100

pub_type

杂志文章

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