PIGG gene mutation associated with Uner Tan syndrome: A first case report

Gautam Wali; Gurusidheshwar M Wali; Carolyn M Sue

doi:10.4103/AOMD.AOMD_28_21

CASE REPORTS

Year : 2021 | Volume : 4 | Issue : 3 | Page : 157-160

PIGG gene mutation associated with Uner Tan syndrome: A first case report

Gautam Wali¹, Gurusidheshwar M Wali², Carolyn M Sue¹
¹ Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St. Leonard’s, New South Wales, Australia
² Neurospecialities Centre, Belgaum, Karnataka, India

Date of Submission	09-Jun-2021
Date of Decision	06-Aug-2021
Date of Acceptance	27-Aug-2021
Date of Web Publication	22-Dec-2021

Correspondence Address:
Dr. Gurusidheshwar M Wali
Neurospecialities Center, Belgaum - 590 001, Karnataka.
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_28_21

Abstract

Uner Tan syndrome (UTS) is a rare neurogenetic disorder characterized by poor cognition, dysarthric speech, and habitual quadrupedal locomotion, and is associated with cerebellar hypoplasia. Mutations in the VLDLR, CA8, WDR81, ATP8A2, and TUBB2B genes are commonly associated with UTS. However, here, we report the case of a patient presenting with quadrupedal locomotion and other clinical features similar to UTS caused by a mutation in the PIGG gene. To the best of our knowledge, this is the first case in which a mutation in the PIGG gene is associated with UTS. We believe that our finding will help broaden the genetic spectrum of the syndrome.

Keywords: PIGG gene, quadrupedal locomotion, Uner Tan syndrome

How to cite this article:
Wali G, Wali GM, Sue CM. PIGG gene mutation associated with Uner Tan syndrome: A first case report. Ann Mov Disord 2021;4:157-60

How to cite this URL:
Wali G, Wali GM, Sue CM. PIGG gene mutation associated with Uner Tan syndrome: A first case report. Ann Mov Disord [serial online] 2021 [cited 2023 May 29];4:157-60. Available from: https://www.aomd.in/text.asp?2021/4/3/157/333362

Introduction

Habitual quadrupedal gait, commonly observed in non-human primates, is a rare and unusual form of locomotion in human beings. In humans, it was first described as a trait of the Uner Tan syndrome (UTS), in which affected individuals ambulated using their palms and feet.^[1] In addition to quadrupedal locomotion, individuals with UTS experience other neurological complexities such as impaired cognition, dysarthric speech, and cerebellar hypoplasia. To date, mutations in the VLDLR, CA8, WDR81, ATP8A2, and TUBB2B genes are known to be associated with UTS.^[2] In our report, we present the case of a patient exhibiting quadrupedal locomotion and other clinical features similar to UTS caused by a mutation in the PIGG gene. To the best of our knowledge, ours is the first study to report the association of the PIGG gene with quadrupedal locomotion.

Case Report

We have previously described a video document of two Indian families (A and B) with quadrupedal locomotion resembling UTS; however, we did not have their genetic information [Video 1].^[3] Since then, we have identified a pathogenic variant in one of the two families. Clinical exome sequencing of the proband from the consanguineous family A (MedGenome) identified a homozygous two-base pair deletion in exon 12 of the PIGG gene (chr4:527659_527660 del) in Case IV-2 [Figure 1]. This deletion results in a frameshift mutation and premature truncation of the protein downstream to codon 875 (p.Leu875Ter; ENST00000453061.2). The variant observed in our case has previously been reported (as p.Leu867Ter) in a patient affected with mental retardation-53.^[4] Sanger sequencing of the proband [Figure 2], Case IV-2], asymptomatic parents [[Figure 2], Cases III-1 and III-2], and younger brother [[Figure 2], Case IV-3] showed that they had the same gene variant but in the heterozygous state. Clinical exome sequencing of family B did not identify any pathogenic variants.

Figure 1: Family pedigree. The family is consanguineous. Proband: Case IV-2 (solid circle)

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Figure 2: Sequence chromatogram showing the variation in exon 12 of the PIGG gene (chr4:527659_527660delTA; c.2624_2625del; p.Leu875Ter) detected in the homozygous state in the proband and in the heterozygous state in the parents and the sibling

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Clinically, the proband displayed global developmental delay, facial dysmorphism, pes planus, non-progressive cerebellar ataxia, gross mental retardation, and almost no speech. Pyramidal signs were absent. She had history of two isolated seizures during childhood. She developed quadrupedal locomotion by the age of 6 years [Video 1]^[3 and brief stretches of bipedal locomotion by the age of 11 years. The quadrupedal locomotion was habitual],[ and was characterized by diagonal sequencing of the limbs using palmigrade placement of the upper extremities. Brain magnetic resonance imaging (MRI) revealed cerebellar hypoplasia and simplification of the cortical gyri [Figure 3].

Figure 3: Magnetic resonance imaging revealing cerebellar hypoplasia and simplification of the cerebral cortex of the proband (Case IV-2)

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Discussion

The genetic],[ neuroimaging],[ and clinical presentations (except quadrupedal locomotion) caused by the PIGG gene mutation in our case are in accordance with the descriptions of PIGG gene mutations in previous studies. Makrythanasis et al. reported five individuals with PIGG gene mutations from two consanguineous families from Egypt],[ two consanguineous families from Pakistan],[ and one non-consanguineous family from Japan. These individuals displayed intellectual disability],[ hypotonia],[ and early-onset seizures. None of the families exhibited quadrupedal locomotion. This finding is in accordance with that in our case],[ which proved that the affected individuals from consanguineous families had homozygous mutations. Brain MRI showed normal findings in the Japanese individual],[ a thin corpus callosum and asymmetry of the lateral ventricles in both Egyptian individuals],[ and cerebellar hypoplasia and mild cerebral atrophy in both Pakistani individuals. Similar to the affected individuals from the consanguineous families],[ the individual in our case also showed evidence of cerebellar hypoplasia and simplification of the cortical gyri.

The PIG gene family is involved in the biosynthesis of glycosylphosphatidylinositol (GPI).^[5] GPI-anchored proteins are a class of lipid-anchored membrane proteins that are ubiquitously expressed on the surface of eukaryotic cells.^[6] GPI-anchored proteins are functionally diverse. Among other cell functions, they have been shown to play an important role in embryogenesis,^[7] neurogenesis,^[8] and prion disease pathogenesis.^[9,10] Considering the essential role of PIG genes in GPI biosynthesis, it is plausible that a sect of GPI-anchored proteins may lead to the disease pathology; however, the mechanism by which this occurs remains to be elucidated.

In conclusion, the identified PIGG gene mutation will help broaden the genetic profile of this unique and rare syndrome.

Author contribution

(1) Conception, organization, and execution of the research project: GW and GMW

(2) Writing of the first draft: GMW and GW

(3) Review and critique: GW and CMS

Ethical compliance statement

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

The authors confirm that the approval of an institutional review board was not required for this work.

Informed consent was obtained from the individual.

Financial support and sponsorship

Financial disclosures for the previous 12 months: G. W has received grant funding from the Hereditary Spastic Paraplegia Foundation, Australia, and the Spastic Paraplegia Foundation, USA, for hereditary spastic paraplegia research.

Conflicts of interest

There are no conflicts of interest to declare.

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