AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders

Enza Maria Valente, Francesco Brancati, Jennifer L. Silhavy, Marco Castori, Sarah E. Marsh, Giuseppe Barrano, Enrico Bertini, Eugen Boltshauser, Maha S. Zaki, Alice Abdel-Aleem, Ghada M H Abdel-Salam, Emanuele Bellacchio, Roberta Battini, Robert P. Cruse, William B. Dobyns, Kalpathy S. Krishnamoorthy, Clotilde Lagier-Tourenne, Alex Magee, Ignacio Pascual-Castroviejo, Carmelo D. SalpietroDean Sarco, Bruno Dallapiccola, Joseph G. Gleeson

Research output: Contribution to journalArticle

Abstract

Objective: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. Methods: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. Results: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. Interpretation: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.

Original languageEnglish
Pages (from-to)527-534
Number of pages8
JournalAnnals of Neurology
Volume59
Issue number3
DOIs
Publication statusPublished - Mar 2006

Fingerprint

Mutation
Genes
Tooth
Nervous System Malformations
Consanguinity
Rhombencephalon
Brain Diseases
Mutation Rate
Missense Mutation
Mesencephalon
Joubert syndrome 1
Central Nervous System
Kidney
Liver

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. / Valente, Enza Maria; Brancati, Francesco; Silhavy, Jennifer L.; Castori, Marco; Marsh, Sarah E.; Barrano, Giuseppe; Bertini, Enrico; Boltshauser, Eugen; Zaki, Maha S.; Abdel-Aleem, Alice; Abdel-Salam, Ghada M H; Bellacchio, Emanuele; Battini, Roberta; Cruse, Robert P.; Dobyns, William B.; Krishnamoorthy, Kalpathy S.; Lagier-Tourenne, Clotilde; Magee, Alex; Pascual-Castroviejo, Ignacio; Salpietro, Carmelo D.; Sarco, Dean; Dallapiccola, Bruno; Gleeson, Joseph G.

In: Annals of Neurology, Vol. 59, No. 3, 03.2006, p. 527-534.

Research output: Contribution to journalArticle

Valente, EM, Brancati, F, Silhavy, JL, Castori, M, Marsh, SE, Barrano, G, Bertini, E, Boltshauser, E, Zaki, MS, Abdel-Aleem, A, Abdel-Salam, GMH, Bellacchio, E, Battini, R, Cruse, RP, Dobyns, WB, Krishnamoorthy, KS, Lagier-Tourenne, C, Magee, A, Pascual-Castroviejo, I, Salpietro, CD, Sarco, D, Dallapiccola, B & Gleeson, JG 2006, 'AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders', Annals of Neurology, vol. 59, no. 3, pp. 527-534. https://doi.org/10.1002/ana.20749
Valente, Enza Maria ; Brancati, Francesco ; Silhavy, Jennifer L. ; Castori, Marco ; Marsh, Sarah E. ; Barrano, Giuseppe ; Bertini, Enrico ; Boltshauser, Eugen ; Zaki, Maha S. ; Abdel-Aleem, Alice ; Abdel-Salam, Ghada M H ; Bellacchio, Emanuele ; Battini, Roberta ; Cruse, Robert P. ; Dobyns, William B. ; Krishnamoorthy, Kalpathy S. ; Lagier-Tourenne, Clotilde ; Magee, Alex ; Pascual-Castroviejo, Ignacio ; Salpietro, Carmelo D. ; Sarco, Dean ; Dallapiccola, Bruno ; Gleeson, Joseph G. / AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. In: Annals of Neurology. 2006 ; Vol. 59, No. 3. pp. 527-534.
@article{96e8ddbd9d5144c998d7294738cd30ab,
title = "AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders",
abstract = "Objective: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain {"}molar tooth{"} sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. Methods: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. Results: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. Interpretation: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.",
author = "Valente, {Enza Maria} and Francesco Brancati and Silhavy, {Jennifer L.} and Marco Castori and Marsh, {Sarah E.} and Giuseppe Barrano and Enrico Bertini and Eugen Boltshauser and Zaki, {Maha S.} and Alice Abdel-Aleem and Abdel-Salam, {Ghada M H} and Emanuele Bellacchio and Roberta Battini and Cruse, {Robert P.} and Dobyns, {William B.} and Krishnamoorthy, {Kalpathy S.} and Clotilde Lagier-Tourenne and Alex Magee and Ignacio Pascual-Castroviejo and Salpietro, {Carmelo D.} and Dean Sarco and Bruno Dallapiccola and Gleeson, {Joseph G.}",
year = "2006",
month = "3",
doi = "10.1002/ana.20749",
language = "English",
volume = "59",
pages = "527--534",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "3",

}

TY - JOUR

T1 - AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders

AU - Valente, Enza Maria

AU - Brancati, Francesco

AU - Silhavy, Jennifer L.

AU - Castori, Marco

AU - Marsh, Sarah E.

AU - Barrano, Giuseppe

AU - Bertini, Enrico

AU - Boltshauser, Eugen

AU - Zaki, Maha S.

AU - Abdel-Aleem, Alice

AU - Abdel-Salam, Ghada M H

AU - Bellacchio, Emanuele

AU - Battini, Roberta

AU - Cruse, Robert P.

AU - Dobyns, William B.

AU - Krishnamoorthy, Kalpathy S.

AU - Lagier-Tourenne, Clotilde

AU - Magee, Alex

AU - Pascual-Castroviejo, Ignacio

AU - Salpietro, Carmelo D.

AU - Sarco, Dean

AU - Dallapiccola, Bruno

AU - Gleeson, Joseph G.

PY - 2006/3

Y1 - 2006/3

N2 - Objective: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. Methods: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. Results: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. Interpretation: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.

AB - Objective: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. Methods: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. Results: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. Interpretation: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.

UR - http://www.scopus.com/inward/record.url?scp=33644821331&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33644821331&partnerID=8YFLogxK

U2 - 10.1002/ana.20749

DO - 10.1002/ana.20749

M3 - Article

C2 - 16453322

AN - SCOPUS:33644821331

VL - 59

SP - 527

EP - 534

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 3

ER -