Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F21%3A10427647" target="_blank" >RIV/00064203:_____/21:10427647 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11130/21:10427647

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=yPEbifoq5C" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=yPEbifoq5C</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/brain/awab041" target="_blank" >10.1093/brain/awab041</a>

Result language

angličtina

Original language name

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Original language description

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2021

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Brain

ISSN

0006-8950

e-ISSN

—

Volume of the periodical

144

Issue of the periodical within the volume

5

Country of publishing house

GB - UNITED KINGDOM

Number of pages

13

Pages from-to

1422-1434

UT code for WoS article

000710927500029

EID of the result in the Scopus database

2-s2.0-85109028619